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

Abstract

Neointimal hyperplasia, a pathological response to arterial interventions or injury, often leads to restenosis and recurrent narrowing or occlusion, particularly in the peripheral vasculature. Its prevalence and negative impact on the long‐term success of vascular interventions have driven extensive research aimed at better understanding the condition and developing effective therapies. This review provides a comprehensive overview of emerging bioengineering strategies for treating neointimal hyperplasia in peripheral vessels. These approaches include novel therapeutics and cell‐based technologies designed to promote re‐endothelialization, modulate vascular smooth muscle cell (VSMC) phenotype, reduce inflammation, scavenge reactive oxygen species (ROS), and enhance biomechanical compatibility between grafts and native vessels. Furthermore, advanced therapeutic delivery modalities are highlighted for their potential to achieve targeted, localized treatment at injury sites. This review also explores underrepresented therapeutic targets beyond traditional approaches, offering new opportunities for intervention. The multifaceted examination underscores the challenge of neointimal hyperplasia and presents a promising roadmap toward more effective treatments, ultimately aiming to improve patient outcomes after vascular interventions.

This review highlights emerging bioengineering strategies for treating neointimal hyperplasia in the peripheral vasculature, focusing on approaches that promote re‐endothelialization, modulate smooth muscle cell phenotype, reduce inflammation, mitigate oxidative stress, and optimize biomechanical compliance. Innovative therapeutic delivery systems are also discussed, offering a comprehensive perspective on current challenges and opportunities for future clinical translation.

1. Introduction

In the United States alone, over 7.9 million patients each year will undergo a cardiovascular intervention such as stent insertion or graft bypass.^{[ 1 ]} Whether endovascular or open surgical intervention, manipulation of arteries and veins leads to neointimal hyperplasia—a complex and heterogeneous process influenced by the intervention type, vascular location, and patient comorbidities. While drug‐eluting stents and balloons have been successfully translated into coronary artery interventions to maintain patency, similar advancements for peripheral vascular interventions have lagged behind.^{[ 2 ]} Pathologic neointimal hyperplasia within the peripheral vasculature can lead to luminal obstruction, reconstruction failure, and downstream ischemia with devastating clinical sequelae such as limb loss or allograft failure.

This review aims to provide a comprehensive understanding of the evolving landscape of neointimal hyperplasia treatment specifically as it relates to the peripheral vasculature. It offers insights into the diverse bioengineering approaches taken to combat this challenging condition, encompassing novel technologies targeting specific aspects of neointimal hyperplasia and innovative therapeutic delivery techniques (Figure 1 ). Moreover, it discusses an intriguing exploration of therapeutic strategies borrowed from other disciplines. The next sections will delve deeper into these topics, aiming to provide a roadmap for engineers and clinicians alike to navigate the intricate path toward clinical success in the treatment of neointimal hyperplasia within the peripheral vasculature.

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.

2. Current Understanding and Clinical Management

Regardless of intervention modality, all revascularization procedures result in vascular injury with an inflammatory response. While this inflammation begins as a beneficial reparative process, the consequent platelet activation and downstream vascular smooth muscle cell (VSMC) proliferation can lead to luminal narrowing and ultimate failure of vascular interventions.^{[ 3 ]} This process, termed neointimal hyperplasia, is the most common cause of mid‐term stenosis of endovascular interventions, such as angioplasty or stenting, as well as open surgical intervention including bypass graft surgery.^{[ 4 ]} It is defined by the accumulation of fibroblasts, VSMCs, and extracellular matrix (ECM) deposition within the intimal layer, creating the neointima responsible for luminal compromise (Figure 2 ).^{[ 4b ]}

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.

Neointimal hyperplasia is present in all forms of vascular intervention, although its severity and ease of treatment differ based on the vasculature, the type of intervention, and even the comorbidities the patient may have. Vascular grafts usually fail at the anastomosis site due to a combination of vascular manipulation and high shear stress due to redirected blood flow, as well as compliance mismatch and suture stresses at the anastomosis site.^{[ 5 ]} In‐stent restenosis due to endovascular interventions is often caused by endothelial denudation and balloon inflation directly injuring the vascular smooth muscle cells,^{[ 6 ]} which in the peripheral vasculature is often resistant to the common drug‐eluting paclitaxel and sirolimus stents commonly used in coronary arteries, in part due to its antiproliferative effects inhibiting adequate re‐endothelialization.^{[ 7 ]} Additionally, patients with comorbidities such as diabetes have worse long‐term patency of stents and grafts within the peripheral vasculature, while their long term patency in the coronary vasculature is comparable to non‐diabetic patients.^{[ 8 ]}

Generally, the initial trigger for neointimal hyperplasia development is endothelial denudation, secondary to vascular injury including wall stretching during angioplasty, surgical manipulation during endarterectomy, or bypass graft implantation. This is followed by endothelial cell (EC) activation and dysregulation of endothelial nitric oxide synthase (eNOS), platelet adhesion and thrombus formation, leukocyte recruitment, and ultimate migration of VSMCs to the intimal layer to form a neointima.^{[ 9 ]} Macrophages contribute to this observed cell migration via the secretion of inflammatory cytokines such as IL‐6 and IL‐8, generation of reactive oxygen species, and production of matrix metalloproteinases thereby facilitating cell migration.^{[ 4} , ^{10 ]} The predominant cell types within the neointima are VSMCs. Although the exact source of the VSMCs is not known, there are a few hypotheses as to their origin. After vascular injury, medial VSMCs exhibit significant apoptosis with resultant rapid repopulation.^{[ 11 ]} The repopulated VSMCs demonstrate significant dedifferentiation from a mature contractile phenotype to a synthetic phenotype marked by increased cellular migration, proliferation, and cytoskeletal and contractile protein synthesis.^{[ 12 ]} Other hypotheses include circulating bone marrow derived vascular progenitor cells differentiating into both ECs and VSMCs in response to vascular injury and medial VSMC apoptosis, transdifferentiation of existing ECs into a more myofibroblast phenotype, or the migration and differentiation of adventitial fibroblasts to a myofibroblast phenotype, all of which may contribute to the developing neointima.^{[ 10} , ^{13 ]}

Efforts to modulate neointimal hyperplasia in the peripheral vasculature have had limited clinical success, with ≈50% of treated vessels developing restenosis within one year due to neointimal hyperplasia.^{[ 14 ]} Surgeons and interventionalists use meticulous techniques to minimize arterial trauma and employ adjuncts, such as vein cuffs, to reduce anastomotic stenosis and graft occlusion. Pharmacological agents aim to inhibit key pathways involved in neointimal development, although their primary purposes are different. Anti‐platelet agents (e.g., aspirin, dipyridamole, ticlopidine) are routinely used postoperatively to prevent thrombotic events, not directly to prevent neointimal hyperplasia, though they may have secondary effects in reducing it.^{[ 15 ]} Statins are primarily prescribed to reduce plaque burden and improve lipid profiles, with secondary benefits of reducing inflammation and potentially attenuating neointimal hyperplasia.^{[ 16 ]} Other agents target VSMC proliferation and migration via inhibition of pathways such as the renin‐angiotensin system or calcium channels.^{[ 15b ]} Anticoagulant‐coated grafts have demonstrated benefits in preclinical models and are employed in clinical practice primarily to prevent thrombosis, with secondary effects in reducing anastomotic hyperplasia.^{[ 17 ]}

Drug‐eluting technology in peripheral vascular disease has been limited to paclitaxel, with more recent use of sirolimus‐eluting stents showing mixed efficacy.^{[ 7} , ¹⁸ , ^{19 ]} These agents are nonspecific, affecting multiple cell types, including endothelial and immune cells, which impair vascular healing. Their efficacy is also limited to the drug elution period, leaving vessels vulnerable to restenosis afterward. Gene therapy approaches have similarly had limited clinical success, with studies like the E2F transcription factor decoy edifoligide trial failing to reduce vein graft failure rates.^{[ 20 ]} These challenges underscore the need for more selective agents that can target key pathways while promoting endothelial recovery, as well as improved delivery methods to extend therapeutic duration and precision. Novel bioengineering strategies could improve outcomes and vessel patency through advanced design to promote vessel healing and prevent neointimal hyperplasia formation.

3. Targeted Bioengineering Strategies for Neointimal Hyperplasia

Neointimal hyperplasia is a multifaceted pathological process characterized by endothelial injury, excessive VSMC proliferation, chronic inflammation, ROS accumulation, and/or biomechanical mismatches. Current clinical treatments often fail to address these diverse factors comprehensively, highlighting the need for innovative bioengineering strategies that target each aspect. By developing targeted therapies that engage with these complex pathways, we can enhance existing treatments and expand the therapeutic landscape to more effectively mitigate neointimal hyperplasia (Table 1 ).

Table 1.

Overview of Biological Targets in Neointimal Hyperplasia, Targeting Strategies, Evaluation Methods, and Key Research Findings.

Target	Therapeutics	Preclinical Model	Summary of Key Findings	Ref.
Promoting Re‐endothelialization	MSCs	Rabbit Carotid Balloon Angioplasty	Significant decrease in neointimal thickness, and a significant increase in endothelial coverage	[23]
	MSC‐Exo	Rat Carotid Balloon Angioplasty	Increase in re‐endothelialization, decrease in intima/media ratio	[24]
	EPCs	Rat Ischemic Stroke	Significant decrease in intima/media ratio, increase in eNOS expression	[25]
		Rat Carotid Balloon Angioplasty	Increase in re‐endothelialization, increase in EPC paracrine signals (VEGF, IGF‐1)	[26]
	Omentin‐1 transfected EPCs	Rat Carotid Balloon Angioplasty	Decrease in neointimal area, increased endothelial proliferation	[27]
	EPC‐Exo	Rat Carotid Balloon Angioplasty	Increase in endothelialization, decrease in intima/media ratio	[28]
		Rat Carotid Balloon Angioplasty	Increase in re‐endothelialization and decrease in neointimal thickening	[29]
	Fibronectin and SDF‐1α modified ePTFE graft	Sheep Carotid Interposition Model	Increase in the attraction of circulating stem cells, increase in endothelialization	[30]
	Rosuvastatin‐loaded stent	Rabbit Femoral Artery Stent Implantation	Improvement in endothelial alignment and endothelial coverage	[31]
	Ticagrelor‐loaded stent	Rabbit Femoral Artery Stent Implantation	Decrease in neointimal thickness, increase in endothelial coverage	[32]
Modulating VSMC Phenotype	MSCs	Rat Carotid Balloon Angioplasty	Decrease in neointima thickness, increase in quiescent VSMCs	[33]
	MSC‐Exo	Rat Carotid Balloon Angioplasty	Decrease in neointimal thickness, decrease in VSMC proliferation and migration	[34]
		Rat Abdominal Aortic Stent Implantation	Significant decrease in intimal thickness, increase in α‐SMA positive VSMCs	[35]
	Tropoelastin	Mouse Infra‐Renal Aortic Interposition	Significant decrease in intimal thickness, significant decrease in actively proliferating VSMCs	[36]
	Biomimetic Heparan Sulfate‐coated ePTFE graft	Sheep Carotid Bypass Graft Implantation	Decrease in neointimal thickness at the anastomosis site, increase in VSMC coating throughout the graft	[37]
	Heparin and MK2i coated PCL graft	In vitro Testing Alone	Decrease in VSMC migration, downregulation of proliferation proteins	[38]
	Atorvastatin	Mouse Carotid Ligation	Decrease in neointimal thickness, direct targeting to VSMCs in media	[39]
Suppressing Pro‐Inflammatory Cascades	MSCs	Mini‐Pig Carotid Stent Deployment	Decrease in intimal thickness, decrease in pro‐inflammatory markers	[40]
		Rat Aortic Patch Model	Decrease in neointimal area, increase in CD68+ macrophages	[41]
	Tacrolimus	Rat Aortic Partial Resection	Decrease in neointimal hyperplasia at the anastomosis site, decrease in pro‐inflammatory immune cell infiltration	[42]
	RvD1 and RvD2	Rabbit Femoral Artery Balloon Angioplasty	Decreased immune cell recruitment, decreased pro‐inflammatory cytokine expression	[43]
	HIFU	Atherosclerotic Pig Model	Decreased atherosclerotic plaque, no damage to endothelium	[45]
	SDT	Rabbit Carotid Balloon Angioplasty	Reduced recruitment of macrophages, reduced intimal area	[46]
Mitigating Oxidative Stress	Retinoic Acid	Rat Abdominal Aortic Interposition	Decreased neointimal thickness, decreased macrophage infiltration	[48]
	Ascorbic Acid	Guinea Pig Aortic Interposition	Decreased platelet aggregation and intimal thickness	[49]
	Glutathione	In vitro Testing Alone	Increased ROS scavenging, superior VSMC cytocompatibility	[50]
	Butyrate	Mouse Femoral Artery Wire Injury	Decreased intimal thickness	[52]
	NO	Rabbit Iliac Artery Stent Implantation	Decrease in ROS at injury site, improved re‐endothelialization	[54]
		In vitro Testing Alone	Generation of NO similar to healthy ECs, excellent cytocompatibility	[55]
		In vitro Testing Alone	Excellent compatibility with VSMCs, improved ROS scavenging ability	[56]
Optimizing Biomechanical Compliance	Heparinized polymer‐ECM grafts	Rat Abdominal Aortic Interposition	Improvement in endothelialization and decrease in intimal thickening compared to standard grafts	[59]
	Gelatin‐PCL grafts	Rat Abdominal Aortic Interposition	Improvement in cell infiltration and integration with native vasculature	[58]

3.1. Promoting Re‐Endothelialization

The endothelium plays a critical role in preventing thrombus formation, regulating nutrient and oxygen transfer to the vessel wall, and maintaining steady laminar flow within blood vessels. However, during vascular interventions, the endothelium is often disrupted or removed, initiating the inflammatory cascade which eventually leads to vascular remodeling and neointima formation, as discussed previously.^{[ 21 ]} A number of early studies provided critical insights into techniques to promote rapid re‐endothelialization, such as cell seeding and bioactive coatings for synthetic grafts.^{[ 22 ]} Their foundational efforts have paved the way for subsequent innovations in re‐endothelialization approaches. To build on these contributions, recent bioengineering strategies focus on promoting re‐endothelialization of injured vessels or preserving the existing endothelium during surgery. These approaches aim to prevent the initial inflammatory cascade that triggers pathological remodeling and, over time, mitigate the risk of restenosis.

Tissue engineering approaches have explored the use of living cells and cell‐derived products to re‐endothelialize vascular devices and mitigate neointimal hyperplasia. Among various cell types, mesenchymal stem cells (MSCs) are of particular interest for their regenerative properties. Studies show that MSCs, delivered locally or systemically, can accelerate re‐endothelialization and reduce intimal hyperplasia. For example, Kim et al. demonstrated that perivascular application of human umbilical cord MSCs significantly increased re‐endothelialization in a rabbit model, reducing the intima/media ratio.^{[ 23 ]} MSC‐derived exosomes (MSC‐Exo) have similarly shown promise: Liu et al. reported that MSC‐Exo administered via tail vein promoted rapid re‐endothelialization and reduced intima/media ratio within two weeks, likely through Erk1/2 pathway activation.^{[ 24 ]} Endothelial progenitor cells (EPCs) also offer potential due to their ability to secrete growth factors, reduce inflammation, and alleviate oxidative stress. Intravenous delivery of EPCs reduced intima/media ratios by 50% in a rat ischemic stroke model,^{[ 25 ]} similar to results from a rat carotid balloon injury model in which EPCs adherence to injured vessels promoted re‐endothelialization and inhibited neointimal hyperplasia.^{[ 26 ]} Genetic modifications further enhance EPC functionality, as Xiang et al. demonstrated with omentin‐1‐transfected EPCs, which reduced inflammation and improved endothelial proliferation.^{[ 27 ]} EPC‐derived exosomes (EPC‐Exo) present an additional promising approach, utilizing potential bioactive mechanisms without the complications of live cells. In a rat carotid injury model, Kong et al. reported that intravenous delivery of EPC‐Exo promoted endothelial cell proliferation and improved intima/media ratios by day 14.^{[ 28 ]} Similar results were found with umbilical cord blood‐derived EPC‐Exo, which enhanced re‐endothelialization and further reduced neointimal hyperplasia by days 14 and 21.^{[ 29 ]} These findings indicate that EPC‐Exo could provide a potent cell‐derived therapy for re‐endothelialization and neointimal hyperplasia prevention.

In addition to cellular therapeutics, the modification of vascular devices with bioactive molecules to recruit host endothelial cells has also been explored. For example, De Visscher et al. modified polyester small diameter grafts with fibronectin and stromal cell derived factor 1 alpha (SDF1α) to promote recruitment and recellularization of the graft in vivo.^{[ 30 ]} In a sheep carotid interposition model, the fibronectin‐coated grafts showed complete endothelialization at the anastomoses and partial endothelialization at the graft center, with significantly reduced neointimal thickness compared to non‐modified grafts. These findings suggest that fibronectin, combined with SDF1α, can effectively modulate endothelial cell recruitment without promoting a synthetic phenotype in VSMCs, thus reducing neointimal hyperplasia formation.

Although not the main mechanism of action, statins such as rosuvastatin and ticagrelor showed promise in improving stents by improving re‐endothelialization after stent insertion. For instance, Lee et al. loaded rosuvastatin in a poly(lactic‐co‐glycolic acid) (PLGA) coating around a stent to attenuate neointimal hyperplasia formation after stent insertion.^{[ 31 ]} Rosuvastatin is a potent statin and has documented secondary effects that promote endothelial function.^{[ 31 ]} In vivo deployment of the stent in the descending abdominal aorta of rabbits showed no thrombus formation up to 1‐month post‐implantation and almost complete re‐endothelialization of the stent struts. ECs along the stent struts were aligned with blood flow and maintained close contact with each other, similar to the native endothelium. ECs exposed to the rosuvastatin‐eluting stent also had increased expression of heme oxygenase 1, a cytoprotective marker upregulated in response to stress. Ticagrelor, an inhibitor of platelet activation has also been linked to improved endothelial function and protection.^{[ 32 ]} Ticagrelor incorporated into a PLGA coating on a metal stent allowed for controlled release, and evaluation in a rabbit aortic insertion model exhibited superior endothelialization compared to sirolimus eluting stents, potentially due to ticagrelor exerting protective effects, while sirolimus is antiproliferative that can prevent endothelialization. Additionally, the endothelium‐dependent vasodilatory response was superior in arteries treated with the ticagrelor‐eluting stent compared to the sirolimus eluting stent. By preserving the endothelium and prioritizing endothelialization post‐vascular injury, the intimal hyperplastic response can be blunted to improve long term patency.

While these bioengineering approaches to promote re‐endothelialization are promising, there remain challenges to their translation into clinical practice. One major barrier is the difficulty in achieving consistent, efficient reendothelization at the site of vascular injury. Cell‐based therapies, such as MSCs and EPCs, also face regulatory hurdles, such as ensuring product consistency and safety, particularly when considering autologous or allogenic sources. Furthermore, the durability of the benefits from these re‐endothelialization approaches is yet to be fully understood. While rapid re‐endothelialization is beneficial for reducing early‐stage thrombosis and restenosis, long‐term studies are required to evaluate the stability of the reformed endothelium, the sustained functionality of implanted cells, and the overall impact on vascular healing. Addressing these challenges through preclinical and clinical studies will be crucial in making these innovative technologies viable for clinical adoption. Despite these hurdles, the advances in targeting re‐endothelialization represent a significant leap forward in reducing restenosis and enhancing the long‐term success of vascular interventions.

3.2. Modulating VSMC Phenotype

The phenotypic switch of VSMCs from a quiescent, contractile state to a proliferative, synthetic state is a crucial driver of neointimal hyperplasia in response to vascular manipulation. This switch leads to excessive ECM deposition and subsequent neointima formation. Current local delivery therapeutics have shown limited success in the peripheral vasculature, highlighting the need for more targeted approaches. This section discusses cellular therapies, bioactive molecules, and drug delivery systems aimed at modulating the VSMC phenotype to prevent pathological remodeling.

Cell‐based and cell‐derived therapies represent a promising avenue for modulating VSMC phenotypes to prevent excessive proliferation and migration. Of note, local delivery of MSCs directly to the injury site could reduce neointimal formation more effectively than systemic delivery.^{[ 33 ]} In a rat carotid balloon injury model, perivascular application of MSCs significantly decreased the intima‐media ratio by 30%, reduced proliferating cell presence, and increased cyclin‐dependent kinase inhibitor p27Kip1. These effects were attributed to the paracrine actions of MSCs, which helped regulate VSMC phenotype and suppress hyperplasia. Like EPC‐Exo, MSC‐derived Exo can deliver microRNA to target VSMC phenotype modulation.^{[ 34 ]} MSC‐Exo transfected with miR‐125b mimic were administered via intravenous injection following rat carotid balloon injury, leading to a significant reduction in the intima/media ratio compared to untreated controls. miR‐125b was found to inhibit Myosin‐1E, thereby reducing VSMC migration and proliferation. This highlights the potential of MSC‐Exo to modulate VSMC phenotype through targeted molecular pathways. Exo‐eluting stents are another novel approach to modulate VSMC phenotypes and preventing neointimal hyperplasia in a rat model. MSC‐Exo were conjugated to stents via ROS linkers.^{[ 35 ]} Compared to bare‐metal stents, Exo‐eluting stents reduced neointimal thickness by 86% and provided better strut coverage than traditional drug‐eluting stents, suggesting improved long‐term outcomes in preventing in‐stent restenosis.

Utilizing ECM‐derived proteins and other bioactive molecules has also shown promise in modulating VSMC phenotype by creating an environment that supports a more favorable cellular response. Sugiura et al. developed a resorbable graft coated with tropoelastin, an ECM monomer involved in modulating VSMC phenotype.^{[ 36 ]} In a murine aortic model, the tropoelastin‐coated graft demonstrated decreased neointimal thickness and fewer actively dividing VSMCs compared to the control polymeric graft, highlighting its potential to inhibit VSMC overproliferation. Wulff et al. coated expanded polytetrafluoroethylene (ePTFE) grafts with biomimetic heparan sulfate, which aimed to mimic native vascular conditions.^{[ 37 ]} In a sheep carotid bypass model, the coated grafts showed no neointimal hyperplasia or VSMC recruitment, while uncoated grafts exhibited fibrin deposition and hyperplasia. This indicates the potential of heparan sulfate to promote a more favorable environment for endothelial health while preventing VSMC‐driven hyperplasia. Lee et al. developed a polycaprolactone (PCL) graft modified with heparin and a cell‐penetrating peptide inhibitor of Mitogen Activated Protein Kinase II (MK2i).^{[ 38 ]} Heparin prevented platelet adhesion, while MK2i inhibited VSMC proliferation and migration. Initial in vitro results show promise for this dual‐approach graft in controlling VSMC phenotypic switching, though in vivo testing is still needed. These studies highlight the importance of mimicking the native environment to better modulate VSMC phenotype and prevent neointima formation.

Pharmacological agents targeting VSMC proliferation and phenotype modulation have also been used to reduce neointimal hyperplasia. Previous work has mostly focused on antiproliferative agents such as paclitaxel and sirolimus to inhibit VSMC proliferation. However, their clinical efficacy is limited, as they do not directly address the underlying phenotypic switch of VSMCs. These agents primarily focus on preventing cell proliferation without modulating the synthetic phenotype that drives excessive ECM production and neointima formation. Mylonaki et al. delivered atorvastatin perivascularly using hyaluronic acid gel and PLGA microspheres to prevent neointimal hyperplasia.^{[ 39 ]} Atorvastatin inhibits VSMC proliferation and migration, and the controlled release formulation significantly reduced neointimal thickness in a mouse carotid ligation model. The formulation also successfully permeated the intimal layer of human saphenous vein grafts ex vivo, targeting VSMCs in the media. By better understanding and targeting the phenotypic switch VSMCs undergo as a result of vascular manipulation, neointimal hyperplasia can be better managed to improve long term patency of vascular interventions.

The approaches to modulate VSMC phenotype outlined above show considerable promise for mitigating neointimal hyperplasia, but there are notable barriers to their clinical translation. A significant challenge lies in achieving targeted delivery and precise modulation of VSMC behavior while minimizing off‐target effects. The development of multifunctional biomaterials that can combine selective VSMC inhibition with endothelial protection is a promising strategy but requires rigorous testing to ensure stability, biocompatibility, and safety. Additionally, regulatory hurdles and manufacturing complexities, especially for cell‐based therapies and novel drug‐eluting systems, pose significant challenges for scalability and commercialization. The use of genetically modified cells or nanoparticles may also raise concerns regarding long‐term safety and immunogenicity. Despite these hurdles, targeting VSMC phenotypic modulation remains a key avenue for improving outcomes in patients undergoing vascular interventions, offering the potential for more durable and precise control over neointimal hyperplasia.

3.3. Suppressing Pro‐Inflammatory Cascades

Inflammatory responses play a significant role in the progression of neointimal hyperplasia, particularly through the recruitment of immune cells such as macrophages in response to vascular injury. Reducing inflammation through immunosuppression and other strategies has emerged as a potential solution for mitigating neointimal hyperplasia. This section discusses cellular approaches, bioactive molecules, and innovative bioengineering techniques for modulating inflammation in vascular interventions.

Cellular therapies, particularly those utilizing MSCs, show promise in mitigating the inflammatory response that drives neointimal hyperplasia. Nakazaki et al. evaluated the effects of systemic MSC infusion in a mini pig model of neointimal hyperplasia.^{[ 40 ]} MSCs were administered intravenously after endovascular stent implantation in the carotid and cervical arteries, resulting in a significant reduction of neointimal proliferation compared to placebo. The MSCs appeared to exert their effects by reducing inflammatory responses, as evidenced by decreased expression of growth factors like platelet‐derived growth factor (PDGF‐BB) and anti‐inflammatory agents, including TGF‐β1 and MMP‐9. Sun et al. investigated a novel approach to MSC delivery through a bioinspired patch made from a decellularized fish swim bladder filled with MSCs in a hydrogel.^{[ 41 ]} In a rat aorta model, this “bioinspired” patch significantly reduced neointimal thickness and inflammation compared to patches with material alone. The MSC‐loaded patch also decreased CD68+ cells (indicative of inflammation) and IL‐33+ cells, highlighting its potential to create an anti‐inflammatory microenvironment conducive to reduced neointimal hyperplasia. These studies underscore the ability of MSC‐based therapies to mitigate neointimal hyperplasia by reducing inflammation, supporting re‐endothelialization, and modulating VSMC phenotypic switching.

Immunomodulatory agents have been explored to suppress inflammatory pathways involved in neointimal hyperplasia. For example, tacrolimus‐eluting sutures are a novel localized delivery approach to prevent neointimal hyperplasia at the anastomosis between vein grafts and native vessels.^{[ 42 ]} In a rat abdominal aorta model, these sutures reduced neointimal area by 22% compared to conventional sutures, outperforming even rapamycin‐eluting sutures. The localized delivery system directly addressed immune cell recruitment without compromising suture function or causing thrombosis. Miyahara et al. demonstrated that D‐series resolvins (RvD1 and RvD2) downregulate the expression of pro‐inflammatory genes such as tumor necrosis factor alpha (TNF‐α), vascular cell adhesion molecule 1 (VCAM‐1), and intracellular adhesion molecule 1 (ICAM‐1), with RvD2 showing the most pronounced effects.^{[ 43 ]} In a rabbit femoral artery balloon injury model, RvD2 delivered directly to the injured site resulted in significantly reduced leukocyte infiltration and neointimal formation. These findings suggest that even brief exposure to resolvins can exert a significant anti‐inflammatory effect, though further work is needed to optimize their delivery for long‐term impact.

In addition to the biological and biochemical approaches above, innovative biophysical approaches have been designed to target the inflammatory response locally at the site of vascular injury. For instance, high‐intensity focused ultrasound (HIFU) has been used clinically to treat conditions such as prostate cancer by causing localized coagulative necrosis.^{[ 44 ]} For nonthermal HIFU, the formation of microscopic bubbles exerts shear stress on the tissue, which has the potential for breaking down atherosclerotic plaque and treating neointimal hyperplasia. Studies in swine have shown that HIFU treatment increased the presence of lipid‐containing macrophages and basophils, without damaging the endothelium or causing thrombus formation in healthy arteries.^{[ 45 ]} This suggests that nonthermal HIFU may selectively affect macrophages and reduce inflammation, making it a candidate for treating neointimal hyperplasia. Yao et al. adapted sonodynamic therapy (SDT) to target chronic inflammation in a rabbit femoral artery balloon injury mode^{[ 46 ]} l. SDT reduced macrophage numbers, VSMC presence, and collagen deposition while increasing elastin in the neointima. This approach appears to work by reducing inflammatory cytokine production by macrophages, thus inhibiting VSMC proliferation and remodeling. The precision and non‐invasive nature of SDT could significantly enhance graft and stent patency.

The approaches aimed at suppressing pro‐inflammatory cascades to mitigate neointimal hyperplasia present a promising avenue for therapeutic intervention, but significant barriers to clinical translation remain. One of the main challenges lies in the complexity of the immune response involved in vascular injury, as multiple cell types, including macrophages, neutrophils, and other immune cells, contribute to the inflammatory environment. Ensuring targeted and sustained modulation of these diverse inflammatory pathways without unintended side effects poses a considerable hurdle. The need for specialized delivery systems that can overcome the dynamic blood flow and mechanical stress at vascular injury sites further complicates the translation of these strategies into clinical practice. Overcoming these barriers will require concerted efforts to optimize dosing regimens, delivery methods, and patient selection criteria to ensure consistent and safe therapeutic effects. Furthermore, robust preclinical and clinical trials are needed to establish the safety and efficacy of these approaches in diverse patient populations, including those with comorbidities that may alter inflammatory responses. By addressing these challenges, approaches targeting inflammation could significantly enhance the long‐term success of vascular interventions, reducing restenosis rates and improving patient outcomes.

3.4. Mitigating Oxidative Stress

Oxidative stress, resulting from excessive ROS production, is common following vascular injury and contributes significantly to neointimal hyperplasia. Excess ROS induces early apoptosis of VSMCs, leading to unfavorable vascular remodeling and restenosis.^{[ 47 ]} Various antioxidant compounds, including vitamins, short‐chain fatty acids (SCFAs), and nitric oxide (NO), have shown promise in reducing oxidative stress and mitigating neointimal hyperplasia. This section presents cellular approaches, bioactive molecules, and drug delivery systems designed to scavenge excess ROS and reduce neointimal formation.

Retinoic acid (all‐trans retinoic acid, or atRA) and ascorbic acid have also been utilized to enhance graft performance. Gregory et al. incorporated atRA into a polymeric graft to mitigate neointimal hyperplasia and prolong graft patency.^{[ 48 ]} In a rat aortic model, atRA‐coated grafts demonstrated significantly reduced neointimal formation and increased lumen area compared to controls. Similarly, ascorbic acid was incorporated into a biodegradable polymer, poly(1,8‐octanediol‐co‐citrate‐co‐ascorbate) (POCA), to coat expanded polytetrafluoroethylene (ePTFE) grafts.^{[ 49 ]} In a guinea pig aortic model, POCA‐coated grafts demonstrated significantly reduced platelet adhesion and neointimal area compared to non‐coated grafts. Flis et al. developed small‐diameter blood vessel grafts using poly(1,8‐octanediol‐co‐citrate) with incorporated glutathione, an antioxidant that scavenges free radicals.^{[ 50 ]} The antioxidant capacity of the graft increased with additional glutathione, while VSMC cultures showed excellent cytocompatibility. Although further in vivo analysis is necessary, these antioxidant properties demonstrate potential in attenuating neointimal hyperplasia by reducing oxidative stress. Additionally, the byproducts of dietary fiber digestion, short chain fatty acids (SCFAs), including acetic, propionic, and butyric acid, have been linked to attenuated vascular inflammation and reduced oxidative stress burden.^{[ 51 ]} Noormid et al. demonstrated that systemic administration of butyrate in a mouse femoral artery injury model attenuated neointimal formation.^{[ 52 ]} Antibiotic‐treated mice supplemented with butyrate had significantly lower neointimal formation compared to mice without supplementation, indicating that SCFAs play an important role in reducing neointimal hyperplasia. Given the rapid clearance of SCFAs through liver metabolism, localized delivery may enhance their therapeutic effects.

Nitric oxide (NO) is a crucial signaling molecule generated by ECs that plays a significant role in regulating vascular health.^{[ 53 ]} NO combats oxidative stress by neutralizing ROS, thereby reducing oxidative damage and maintaining vascular homeostasis. However, due to its instability, sustained NO delivery is challenging. Several bioengineering approaches have been developed to achieve localized and sustained NO release at vascular injury sites, providing anti‐inflammatory, anti‐thrombotic, and ROS‐scavenging benefits. Chen et al. developed a hydrogel with a catalytic mechanism to generate NO from endogenous nitrosated thiols.^{[ 54 ]} The NO‐generating hydrogel was coated onto a bare metal stent, allowing continuous NO production directly at the site of vascular injury. In vitro testing with ECs showed that NO generated by the hydrogel promoted re‐endothelialization and scavenged excess ROS, thereby reducing oxidative stress. In a rabbit iliac artery model, NO‐generating stents demonstrated reduced neointimal thickness, improved endothelialization, and minimal inflammation compared to bare metal stents, underscoring the therapeutic potential of NO in combating ROS and inhibiting neointimal hyperplasia. Yu et al. designed a polymeric coating for expanded polytetrafluoroethylene (ePTFE) grafts composed of POCA, which could generate NO by reacting with endogenous S‐nitrosothiols (RSNO) in the bloodstream.^{[ 55 ]} NO generation by POCA‐coated grafts was at a rate similar to that produced by healthy ECs, allowing localized scavenging of ROS and promoting re‐endothelialization while inhibiting VSMC overproliferation. In vitro results demonstrated successful cell adhesion, although further optimization and in vivo testing are needed to determine efficacy. In another study, Zhao et al. developed poly(diol citrate) elastomers that released NO gradually over a period of two days, providing an extended anti‐oxidative effect.^{[ 56 ]} The polymer coated ePTFE grafts demonstrated steady NO release, ROS scavenging, and biocompatibility with VSMCs in vitro, suggesting potential for neointimal hyperplasia inhibition in future in vivo studies. The use of NO as a ROS scavenger highlights its role in maintaining endothelial function, reducing oxidative stress, and promoting vascular healing after injury. Sustained, localized NO delivery has the potential to effectively reduce oxidative damage, making it a promising therapeutic strategy for mitigating neointimal hyperplasia.

The development of therapies aimed at mitigating oxidative stress to reduce neointimal hyperplasia has shown significant promise, yet there are challenges to translating these strategies into clinical practice. One of the major barriers lies in the effective and sustained delivery of antioxidant agents to the injury site. Many antioxidant molecules, such as vitamins and short‐chain fatty acids, are rapidly metabolized or cleared from the body, making it challenging to maintain therapeutic levels at the site of vascular injury. Localized delivery of antioxidants, such as through biodegradable polymers and hydrogels, holds promise for enhancing the therapeutic efficacy of these agents while minimizing systemic side effects. However, ensuring consistent and controlled release of antioxidants that can withstand the physiological conditions of the vasculature is a critical hurdle. Moreover, although many preclinical studies demonstrate reductions in oxidative stress and improvements in vascular remodeling, the heterogeneity of human patients—such as differences in comorbidities, age, and lifestyle factors—can impact the efficacy of these treatments. More translational research is needed to establish the safety and effectiveness of these approaches in diverse patient populations. Additionally, regulatory challenges related to the approval of novel biomaterials and complex delivery systems can further delay clinical implementation. Advancements in materials science and engineering are helping to address these challenges, and continued interdisciplinary efforts are needed to develop delivery systems that can overcome the limitations associated with antioxidant therapies.

3.5. Optimizing Biomechanical Compliance

The mechanical properties of the vasculature, including devices such as vascular stents and grafts can significantly influence the cascade of neointimal hyperplasia.^{[ 57 ]} Mismatch between the mechanical properties of native vasculature and engineered grafts leads to irregular hemodynamics, creating stress‐related injuries at the anastomosis site that promote neointimal hyperplasia.^{[ 5} , ^{58 ]} Novel approaches to improving biomechanical compliance, enhancing graft performance, and reducing hyperplastic responses are at the forefront of scientific exploration. These approaches include the modification of existing vascular graft materials with bioactive molecules and the development of novel materials that are resistant to neointimal hyperplasia.

Jiang et al. previously described a series of strategies to modify ECM‐based arterial grafts via polymer‐ECM hybridization. In a rat abdominal aortic interposition model, they found that heparin‐modified polymer‐ECM grafts significantly reduced neointimal hyperplasia, only when conjugated without chemical crosslinking, demonstrating the importance of mechano‐compatibility to mitigate neointimal hyperplasia.^{[ 59 ]} The heparin‐modified graft also promoted re‐endothelialization and exhibited minimal macrophage infiltration, highlighting the importance of compliance matching in graft design. In a different study, Furdella et al. manipulated the compliance of small‐diameter grafts by altering their composition using gelatin or polycaprolactone (PCL) and modifying crosslinking with genipin.^{[ 58 ]} They tested three grafts: a compliant graft with high gelatin content (CMgel), a non‐compliant graft with high PCL content, and another non‐compliant graft with increased genipin crosslinking. In a month‐long rat aortic interposition model, the CMgel graft had the lowest macrophage infiltration, and VSMCs infiltrating the graft exhibited a more contractile phenotype compared to the non‐compliant grafts. This further indicates that compliance matching is crucial for long‐term patency. Optimizing biomechanical compliance is crucial to improving the performance and patency of synthetic vascular grafts by mitigating neointimal hyperplasia. By addressing compliance mismatch and incorporating bioactive molecules, new and improved grafts can be designed to more closely mimic the properties of native vessels, ultimately benefiting patients in the long run.

Translating the advances in optimizing biomechanical compliance into clinical practice presents several challenges, yet offers significant potential for improving vascular graft outcomes. One of the main barriers lies in the development of materials that adequately balance flexibility, strength, and compatibility with the native vasculature. Native arteries exhibit complex mechanical properties that vary with location, and achieving a graft that accurately replicates these dynamic characteristics is technically challenging. The importance of matching compliance is further underscored by findings that demonstrate significant differences in neointimal hyperplasia based on compliance levels. However, engineering materials that remain durable and flexible in the physiological environment without degrading or causing inflammation is a major hurdle. Another challenge is the scalability and reproducibility of advanced graft modifications. Techniques such as polymer‐ECM hybridization or the incorporation of bioactive molecules have shown promising results in preclinical models, but their scalability for mass production and clinical application must be carefully evaluated. Regulatory requirements for novel graft materials can also pose significant barriers to clinical translation, as the materials must meet stringent safety and efficacy standards for human use. Despite these challenges, optimizing biomechanical compliance represents a promising avenue for improving graft performance and reducing neointimal hyperplasia. Achieving compliance‐matched, biologically integrated vascular grafts will ultimately enhance long‐term patency and patient outcomes following vascular interventions.

4. Advances in Therapeutic Delivery Modalities

Given the complex pathophysiology of neointimal hyperplasia, considerable interest lies not only in the therapeutic agents used but also in the delivery vehicles and modalities that can effectively target and treat neointimal hyperplasia. Traditional drug‐eluting stents (DES), commonly used in peripheral arteries, have faced significant challenges, including hypersensitivity reactions and incomplete re‐endothelialization, which can exacerbate neointimal hyperplasia and compromise long‐term outcomes.^{[ 60 ]} As a result, current research aims to address these complications and prevent restenosis after vascular reconstruction without negatively impacting endothelial recovery. Recent advancements have transformed the field of therapeutic delivery for targeting neointimal hyperplasia in injured vasculature. These novel technologies strive to enhance the specificity, precision, and efficacy of drug delivery, thereby improving therapeutic outcomes while minimizing off‐target effects. This section explores cutting‐edge delivery approaches, including targeted nanoparticles, bioresorbable scaffolds, and innovative gene delivery and electrically conducting systems, that aim to mitigate neointimal hyperplasia while preserving endothelial function.

4.1. Intravascular Modalities

Intravascular approaches to treat neointimal hyperplasia focus on targeted drug delivery strategies that enable localized administration directly to the site of vascular injury. These methods aim to minimize systemic side effects and enhance therapeutic efficacy by concentrating treatment where it is needed most. Micro‐ and nanoparticles are often used as carriers for therapeutic agents, providing precise and controlled drug release specifically to areas affected by neointimal hyperplasia. The refinement of these intravascular techniques is critical to advancing the precision and effectiveness of therapeutic interventions, ultimately improving outcomes for patients undergoing vascular procedures.

For example, Zhu et al. explored the use of paclitaxel‐loaded microbubbles with ultrasound‐triggered drug delivery.^{[ 61 ]} In a rabbit iliac artery restenosis model, the paclitaxel‐loaded microbubbles were injected via ear margin veins, allowing for systemic circulation. Imaging‐guided drug delivery was achieved using two ultrasound transducers: a high‐frequency imaging transducer to identify the restenosis region of the iliac artery and a low‐frequency transducer to induce drug release by destroying microbubbles in the target area. This combined approach led to a significant reduction in neointimal hyperplasia, evidenced by increased lumen area and a reduced intima/media ratio compared to the control group at one week post‐intervention. The ultrasound‐triggered delivery system represents a promising method for precise, controlled drug delivery in vascular interventions.

Another innovative approach is the use of multimodal nanoclusters, developed with platelet membrane coating and ROS‐responsive characteristics, loaded with RVX‐208—a small molecule inhibitor of bromodomain and extra‐terminal (BET) proteins.^{[ 62 ]} In a rat balloon angioplasty model, these ROS‐detonable nanoclusters were injected intravenously via the tail vein. They demonstrated enhanced targetability, improved biodistribution, and deeper penetration into the injured vessel walls, with ROS triggering localized drug release. The treatment group receiving RVX‐loaded nanoclusters showed a significantly lower intima/media ratio and a larger lumen area compared to other treatment groups, suggesting a high level of efficacy for reducing neointimal formation.

Overall, intravascular approaches utilizing micro‐ and nanoparticles represent a cutting‐edge direction in the treatment of neointimal hyperplasia. These technologies hold great promise for achieving precise, localized drug delivery, improving therapeutic outcomes, and reducing complications associated with systemic drug administration in vascular interventions.

4.2. Endovascular Modalities

Endovascular‐focused technologies present promising solutions for optimizing drug delivery strategies to combat neointimal hyperplasia. Their unique features, such as enhanced drug delivery efficiency and the use of bio‐absorbable materials, hold the potential to improve treatment precision and efficacy in vascular surgery. Lee et al. introduced an innovative approach to drug delivery using microneedle drug‐eluting balloons to address the need for sustained delivery of anti‐platelet agents, often required to prevent in‐stent restenosis and thrombosis ^{[ 63 ]} (Figure 3A). This approach involved curing a microneedle array onto a balloon surface and subsequently coating it with Rhodamine B and paclitaxel. The microneedles increased drug delivery efficiency by 2.4 times compared to standard drug‐eluting balloons in vivo. In an atherosclerotic rabbit model, the microneedle drug‐eluting balloon significantly reduced luminal stenosis, including area, diameter stenosis, and intima‐plaque ratio, compared to the standard drug‐eluting balloon group at 4 weeks. This promising technology provides an improved method for delivering therapeutic agents directly to the target site, enhancing local efficacy (Figure 3B).

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.

Another promising endovascular strategy involves bio‐absorbable vascular stents (BVS) with integrated drug delivery. Park et al. developed a 3D‐printed BVS coated with sirolimus for controlled drug release.^{[ 64 ]} In a porcine restenosis model, the sirolimus‐coated BVS exhibited significantly lower area restenosis (20.7%) compared to the non‐coated BVS group (35.9%) at 4 weeks. This approach leverages the biocompatibility and biodegradability of the BVS to deliver drugs in a sustained manner, reducing neointimal hyperplasia while eliminating the long‐term risks associated with permanent stent materials. While endovascular‐focused technologies currently in practice do not fully eliminate the challenges posed by neointimal hyperplasia, especially in peripheral arteries, these advancements are encouraging steps forward in effectively addressing local restenosis. Continued development and refinement of endovascular devices hold the promise of transforming the clinical landscape, and improving long‐term outcomes for patients undergoing vascular interventions.

4.3. Perivascular Modalities

Complementing the array of endovascular approaches, perivascular‐focused technologies have emerged as promising strategies for precise therapeutic delivery. Several innovative approaches have highlighted the potential of perivascular modalities, making them a subject of continued research and exploration. For example, Lee et al. introduced the concept of microneedle cuffs as perivascular delivery devices designed to efficiently deliver therapeutic agents to the tunica media ^{[ 65 ]} (Figure 3C). In a rabbit abdominal aorta balloon injury model (Figure 3D), the microneedle cuffs significantly reduced neointimal hyperplasia, as evidenced by reduced neointimal thickness at both 2 and 4 weeks post‐injury (Figure 3E). This approach showcases the potential of perivascular microneedle technology to target the neointimal hyperplastic response. Another innovative approach involved periadventitial local drug delivery using tissue‐adhesive rapamycin‐loaded unimolecular micelles with N‐hydroxysuccinimide ester (NHS) terminal groups.^{[ 66 ]} In a rat carotid balloon injury model, this method significantly reduced the intima/media ratio by 75.5%, compared to the control group treated with empty micelles. Additionally, the normalized intima thickness and stenosis rate were reduced by 68.9% and 66.6%, respectively, without inducing an inflammatory response typically associated with bulky hydrogels. These rapamycin‐loaded micelles achieved sustainable drug release that effectively reduced neointimal formation, demonstrating its potential to curb neointimal hyperplasia.

Wei et al. developed a tri‐layered hydrogel bio‐patch incorporating PLGA nanoparticles loaded with drugs in each layer for controlled and targeted delivery.^{[ 67 ]} Specifically, the inner layer contained heparin and CD34 antibodies, the middle layer had rapamycin and SB431542, and the outer layer was loaded with Necrostation‐1. In a rat inferior vena cava model, patches were sewn to the vessel and explanted at 2 weeks, showing significantly reduced neointima thickness compared to control patches. The bio‐patch also demonstrated a significant decrease in markers for VSMC presence (α‐actin) and cell proliferation activity (PCNA), suggesting its efficacy in reducing neointimal hyperplasia. Another perivascular approach explored the use of a hyaluronic acid‐dopamine bio‐adhesive gel for rapid atorvastatin release, coupled with biodegradable microparticles for sustained atorvastatin release.^{[ 68 ]} Though animal studies are yet to be conducted, preliminary testing has shown successful biphasic drug release and biocompatibility in rats. The diverse range of perivascular technologies showcases their versatility and potential for targeted drug delivery to mitigate neointimal hyperplasia. These innovations represent exciting opportunities for localized interventions that could enhance long‐term outcomes in patients undergoing vascular procedures.

4.4. Other Approaches

Emerging technologies, such as electrical stimulation and electroporation, are gaining attention in the treatment of neointimal hyperplasia. These techniques are being explored for their potential to modulate cell phenotypes and deliver gene therapies safely to surrounding tissues, offering innovative alternatives to traditional treatment methods.

Derhambakhsh et al. explored electrical stimulation on VSMC phenotype.^{[ 69 ]} In their study, VSMCs were cultured on a decellularized sheep aorta and subjected to electrical stimulation using a 1000 µA sinusoidal electrical current. They observed that electrical stimulation induced conformational changes in vimentin, nestin, and beta‐actin protein expression, leading to a decrease in these proteins. This suggested that VSMCs adopted a more contractile phenotype, rather than the synthetic, proliferative phenotype commonly associated with neointimal hyperplasia. Additionally, the stimulated VSMCs demonstrated better self‐organization and elongation along the graft, mimicking native arterial tissue more closely compared to non‐stimulated VSMCs. Although in vivo testing has not yet been conducted, these findings suggest that electrical stimulation could encourage VSMCs to maintain a contractile phenotype, thereby mitigating neointimal formation and prolonging graft patency.

Ding et al. designed a metal‐polymer external stent (MPS) capable of providing external support to vein grafts while also conducting electricity for electroporation (Figure 4 ).^{[ 70 ]} Electroporation involves applying an electrical current to widen existing pores in the cell membrane, allowing safe gene delivery without viral vectors. The researchers designed plasmids carrying tissue inhibitors of metalloproteinase‐3 (TIMP‐3) genes, which were lyophilized onto the stent to target adventitial fibroblasts infiltrating the graft. In a rabbit jugular vein graft model, electrical stimulation with the MPS significantly inhibited neointimal hyperplasia formation compared to the MPS alone, with minimal damage to surrounding tissues (Figure 4A–C). This approach holds promise for enhancing the clinical viability of gene delivery, making it a potential tool for targeted treatment of neointimal hyperplasia.

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.

Cheng et al. also designed a blood vessel graft using liquid metal and poly(L‐lactide‐co‐ε‐caprolactone) (PLC), making it conductive, and allowing for electrical stimulation and electroporation of recruited cells.^{[ 71 ]} In vivo, testing in a rabbit carotid anastomosis model showed that the graft stayed patent for 3 months post‐implantation and integrated seamlessly with the surrounding tissue. The graft also retained conductivity during implantation, had complete endothelialization, and showed no neointimal hyperplasia formation over 3 months (Figure 4D–G). Electroporation and electrical stimulation show great promise in clinical application for its recruitment of cells and prevention of neointimal hyperplasia.

These novel approaches represent exciting avenues in the field of neointimal hyperplasia treatment, leveraging electric signaling for modulating VSMC behavior and delivering genetic therapies safely. As research progresses, these strategies may offer additional therapeutic options for improving the outcomes of vascular interventions, especially in cases where traditional methods fall short.

5. Challenges and Future Directions

Despite promising advancements in the treatment of neointimal hyperplasia, several challenges remain in translating these innovative strategies into successful clinical outcomes. One of the primary obstacles is the mismatch between animal models used in preclinical research and the complex nature of neointimal hyperplasia in human patients. While animal models provide valuable insights into the mechanisms and potential therapies, they often fail to fully capture the intricacies of the disease as it manifests in humans. Factors such as age, sex, comorbidities, and differences in vascular physiology are often overlooked in preclinical models, contributing significantly to the failure of numerous therapeutic candidates during clinical trials. To bridge this gap, researchers must develop more accurate and representative animal models that mimic the complexities of human disease, thereby increasing the likelihood of successful clinical translation.

Moreover, although several key cell types and processes have been identified in the pathogenesis of neointimal hyperplasia, much remains unknown about the mechanisms of pathological and adaptive remodeling. Dysfunction at the cellular level, such as mitochondrial dysfunction, has been linked to vascular inflammation, endothelial dysfunction, and macrophage activation—offering potential new therapeutic targets that have yet to be fully explored.^{[ 72 ]} Additionally, the crosstalk between different systems, such as sympathetic innervation of arteries, plays a role in modulating VSMC phenotype, with aberrant innervation potentially contributing to the phenotypic switch leading to VSMC over‐proliferation.^{[ 73 ]} Despite these hurdles, the field of neointimal hyperplasia treatment remains dynamic and filled with promise. Ongoing research continues to shed light on the underlying mechanisms driving neointimal hyperplasia, offering new targets for intervention. Additionally, advancements in drug delivery systems and cell‐based therapies hold potential for more effective and sustained treatments. The future of neointimal hyperplasia treatment is likely to witness a convergence of interdisciplinary efforts, drawing inspiration not only from vascular biology but also from fields such as oncology and regenerative medicine. Collaborations between scientists, clinicians, and industry partners will be instrumental in bridging the translational gap and moving closer to clinical success.

Emerging evidence suggests systemic interventions, such as dietary modifications and gut microbiome modulation, may play a significant role in mitigating neointimal hyperplasia. A recent clinical study on short‐term preoperative protein caloric restriction (PCR) showed improved metabolic fitness and reduced ischemia‐reperfusion injury, suggesting dietary interventions may benefit arterial health and reduce neointimal formation.^{[ 74 ]} Additionally, studies have shown that altering the gut microbiota in animal models significantly reduced differences in neointimal hyperplasia outcomes, highlighting the link between the microbiome and vascular remodeling.^{[ 75} , ^{76 ]} Combining PCR with microbiome‐targeted interventions, such as prebiotics or probiotics, could offer a promising strategy for reducing inflammation and promoting vascular health. Integrating these systemic approaches with local bioengineering strategies may provide a more comprehensive solution for preventing neointimal hyperplasia and improving long‐term vascular intervention outcomes.

Emerging technologies offer the potential to address some of the existing challenges and enhance the management of neointimal hyperplasia. Flexible sensors are a promising innovation for the real‐time monitoring of vascular device performance. These sensors can be integrated into vascular grafts and stents to provide continuous data on factors such as flow dynamics, mechanical stress, and local biochemical markers.^{[ 77 ]} This real‐time feedback allows for the early detection of neointimal hyperplasia, potentially enabling timely medical intervention before significant complications occur. Moreover, flexible sensors could be coupled with drug delivery systems to release therapeutics in response to detected changes, enabling more dynamic and responsive treatment strategies. Synthetic biology represents another novel avenue for addressing neointimal hyperplasia. Advances in synthetic biology allow for the design of gene circuits that can be introduced into cells to regulate their behavior in response to environmental cues.^{[ 78 ]} For instance, synthetic gene circuits could be engineered to detect changes in the local inflammatory environment and subsequently activate anti‐inflammatory pathways to mitigate the development of neointimal hyperplasia. Synthetic biology also holds promise for the development of “smart” vascular devices that can self‐adjust in response to changes in the vascular environment, potentially enhancing device longevity and reducing complications. The application of artificial intelligence (AI) is gaining attention for its role in optimizing the treatment of neointimal hyperplasia. AI, particularly machine learning algorithms, can analyze large datasets from preclinical and clinical studies to identify patterns and predict patient outcomes.^{[ 79 ]} By integrating data on patient demographics, comorbidities, genetic factors, and imaging data, AI can help tailor personalized treatment plans that are likely to yield the best outcomes for individual patients. AI can also assist in drug discovery by identifying potential therapeutic candidates based on known molecular targets involved in neointimal hyperplasia.

In conclusion, while significant challenges persist, the journey toward effective neointimal hyperplasia treatment is marked by innovation and determination. With a better understanding of current limitations and a commitment to overcoming them, the field is poised to deliver impactful therapies and improve patient outcomes in the years ahead.

Conflict of Interest

The authors declare no conflict of interest.

Biographies

Nikita Wilson John is a Ph.D. candidate in the Biomedical Engineering program at Northwestern University. She earned her Bachelor of Science in Biomedical Engineering from Rutgers University in 2022, where she was part of the Honors College living‐learning community. Nikita currently conducts research in the Jiang Lab at Northwestern, focusing on therapeutic delivery strategies for vascular diseases. She is a recipient of the T32 RE‐Train fellowship at Northwestern University, which supports her development as a researcher in regenerative medicine and therapeutic innovation.

Bin Jiang is an Assistant Professor of Vascular Surgery and Biomedical Engineering at Northwestern University. She holds a Ph.D. in Biomedical Engineering from the Illinois Institute of Technology and completed her postdoctoral training at Northwestern University. Dr. Jiang's research is centered on vascular regenerative engineering, integrating stem cell engineering, biomaterials science, and synthetic biology to develop innovative therapies for vascular repair and regeneration. Her work bridges fundamental science and translational applications to address unmet clinical needs in vascular health.

Wilson John N., Dang C., Reddy N., Chao C., Ho K. J., Jiang B., Bioengineering Strategies for Treating Neointimal Hyperplasia in Peripheral Vasculature: Innovations and Challenges. Adv. Healthcare Mater. 2025, 14, 2401056. 10.1002/adhm.202401056