[Silver Ion Decreases Foreign Body Reaction and Venous Neointimal Hyperplasia through the Inhibition of Interleukin-33 Expression].

INTRODUCTION: Vascular prosthetic grafts are widely used in vascular surgery; however, graft infection remains a major concern. Silver-coated vascular grafts have demonstrated anti-infection properties in clinical settings; however, whether the silver irons influence foreign body reaction or neointimal hyperplasia remains unclear. METHODS: Sodium alginate and hyaluronic acid (SA/HA) hydrogel patches loaded with rhodamine, with or without silver, were fabricated. Patches were implanted in the subcutaneous or abdominal cavity and inferior vena cava of rats. Samples were harvested on day 14 and examined via immunohistochemical and immunofluorescence analyses. RESULTS: Silver hydrogel was found to decrease the foreign body reaction; after subcutaneous and abdominal cavity implantation in rats, the capsule was found to be thinner in the silver hydrogel group than in the control hydrogel group. The silver hydrogel group had fewer CD68-positive cells and proliferating cell nuclear antigen and interleukin-33 (IL-33) dual-positive cells than the control hydrogel group. Additionally, the silver hydrogel patch reduced the neointimal thickness after patch venoplasty in rats, and the number of IL-33- and IL-1ß-positive cells was lower than that in the control patch. CONCLUSION: Silver-loaded SA/HA hydrogel patches decreased the foreign body reaction and venous neointimal hyperplasia in rats by the inhibition of IL-33 expression.

Wood-Derived Vascular Patches Loaded With Rapamycin Inhibit Neointimal Hyperplasia.

Background: Patches are commonly used to close blood vessels after vascular surgery. Most currently used materials are either prosthetics or animal-derived; although natural materials, such as a leaf, can be used as a patch, healing of these natural materials is not optimal; rhodamine and rapamycin have been used to show that coating patches with drugs allow drug delivery to inhibit neointimal hyperplasia that may improve patch healing. Wood is abundant, and its stiffness can be reduced with processing; however, whether wood can be used as a vascular patch is not established. We hypothesized that wood can be used as a vascular patch and thus may serve as a novel plant-based biocompatible material. Method: Male Sprague-Dawley rats (aged 6-8 weeks) were used as an inferior vena cava (IVC) patch venoplasty model. After softening, wood patches coated with rhodamine and rapamycin were implanted into the rat subcutaneous tissue, the abdominal cavity, or the IVC. Samples were explanted on day 14 for analysis. Result: Wood patches became soft after processing. Patches showed biocompatibility after implantation into the subcutaneous tissue or the abdominal cavity. After implantation into the IVC, the patches retained mechanical strength. There was a significantly thinner neointima in wood patches coated with rapamycin than control patches (146.7 ± 15.32 µm vs. 524.7 ± 26.81 µm; p = 0.0001). There were CD34 and nestin-positive cells throughout the patch, and neointimal endothelial cells were Eph-B4 and COUP-TFII-positive. There was a significantly smaller number of PCNA and α-actin dual-positive cells in the neointima (p = 0.0003), peri-patch area (p = 0.0198), and adventitia (p = 0.0004) in wood patches coated with rapamycin than control patches. Piezo1 was expressed in the neointima and peri-patch area, and there were decreased CD68 and piezo1 dual-positive cells in wood patches coated with rapamycin compared to control patches. Conclusion: Wood can be used as a novel biomaterial that can be implanted as a vascular patch and also serve as a scaffold for drug delivery. Plant-derived materials may be an alternative to prosthetics or animal-based materials in vascular applications.

Outcomes of transcarotid artery revascularization: A systematic review.

BACKGROUND: Ischemic stroke and disability caused by carotid artery stenosis have always been worldwide problems. At present, carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS) have been commonly used to treat carotid artery stenosis. Recently, transcarotid artery revascularization (TCAR) seems to be another option. METHODS: We searched PubMed and Embase to find literatures comparing TCAR with TFCAS and CEA. The primary outcomes were stroke, myocardial infarction (MI), transient ischemic attack (TIA), death, cranial nerve injure (CNI), and operative time. Secondary outcomes were stroke, death, MI in the elderly; cost; radiation; and entry site complication. RESULTS: Initial search of the literature included 165 articles, of which 12 studies were chosen in the end. These studies demonstrated high technical success rate of TCAR. Patients who received TCAR had lower risks of death, stroke/death and less radiation exposure compared to TFCAS. In meta analysis, the risk of stroke was significantly lower in TCAR group than TFCAS (OR 0.63; 95%CI 0.47-0.85). And there was no significant difference in TIA and MI. TCAR was associated with shorter operative time, lower risk of CNI and less blood loss compared to CEA. In older patients, the effect of TCAR was significantly better than that of TFCAS. CONCLUSION: TCAR is associated with a lower risk of perioperative stroke compared to TFCAS. TCAR is also associated with shorter operative time, lower risk of CNI and less blood loss compared to CEA. TCAR may be a promising treatment option besides TFCAS and CEA.

Systematic Review and Meta-Analysis of Published Studies on Endovascular Repair of Abdominal Aortic Aneurysm With the p-Branch.

Background: Endovascular treatment of juxtarenal or pararenal abdominal aortic aneurysms is more popular than open surgery, mainly because it reduces perioperative mortality and morbidity. The custom-made fenestrated devices need to be tailored to each patient, so these devices require extra manufacturing and shipping time. The increased wait time may increase the risk of aneurysm rupture in some patients. In some situations, "Off-the-shelf" (OTS) fenestrated grafts can be used. The Cook Zenith p-Branch device (William Cook Australia, Brisbane, Australia) is a relatively common OTS. This study aimed to systematically evaluate all published experiences with p-Branch. Methods: We searched PubMed, Embase, and Cochrane to find works of literature that reported on the outcomes of patients treated with the p-Branch stent-grafts. Then we conducted an assessment of quality and meta-analysis of the results. The primary endpoints were the application rate of p-Branch stent-graft (type A, B), technical success rate, and early re-intervention rate. We estimated pooled proportions and 95% CIs. Results: Initial search of the literature included 111 articles, of which 7 studies were included in the end. A total of 260 patients were enrolled in these studies, and 218 patients were eventually treated with p-Branch. The pooled application rate of type A devices was 48% (95% CI, 29-67%), and pooled application rate of type B devices was 30% (95% CI, 16-44%). The pooled technical success rate was 87% (95% CI, 75-98%). The early re-intervention rate was 10% (95% CI, 3-17%). Midterm renal infarct rate (after 30 days) was 3% (95% CI, 0-6%). Midterm re-intervention rate (after 30 days) was 30% (95% CI, 3-57%). Midterm renal failure rate (after 30 days) was 6% (95% CI, 2-10%). Conclusions: This pooled analysis indicated an acceptable technical success rate after p-Branch stent-graft implantation, with early and midterm re-intervention rate and renal failure rate that cannot be ignored. The p-Branch repair of juxtarenal abdominal aortic aneurysms may be an appropriate and safe option, especially in emergency situations.

The Current State of Vascular Surgery Presence in Bilibili Video Platform of China.

Background: With the development of the Internet, more and more patients search for disease-related information on video platforms during the treatment process, and physicians also look for learning materials through these video platforms. Bilibili is one of the most popular video platforms in China. This study evaluated information on various interesting topics, and related surgical procedures searched through Bilibili. Method: The Bilibili platform was independently queried for 12 common vascular diseases or related surgical procedures between October and November 2021 by two independent authors using the Baidu search engine. Information about the video and uploader was collected, and descriptive analyses of the overall and first-page results were performed. Results: A total of 3,998 search results were retrieved by searching 12 vascular-related topics, of which 2,225 actual videos (55.7%) were finally confirmed to be related to medicine. Videos for the public accounted for 84.8% of these 2,225 videos. In addition, 50.5% of the video results were uploaded by vascular surgeons, 12.4% by other specialties, 17.7% by organizations, and 19.4% by other individuals. The total number of videos searched for varicose vein and peripheral vascular diseases was the largest, and the total number of leg amputation videos was the smallest. The largest number of videos for medical professionals was about pulmonary embolism, and the smallest was about leg amputation. On the first pages, 168 results (70.0%) were actually medically relevant, and only 7.7% of the videos were uploaded by vascular surgeons. Conclusion: On the Bilibili platform, videos about vascular diseases are extensive but not comprehensive. The videos uploaded by vascular surgeons are rare, and the results searched are not precise. The online presence of vascular surgeons needs to be improved, which may partially solve the problem of low-quality videos due to the lack of strict management and censorship.

Intramural injection of pluronic gel loaded with drugs to alleviate arterial injury.

BACKGROUND: Balloon angioplasty, stent implantation, and application of an arterial clamp during surgery can induce artery injury such as elastin breaks and endothelium injury, but there is little research focused on the injury induced by these therapeutic manipulations. We established a simple and reproducible small animal aortic injury model and examined intramural injection as a potential therapeutic method to alleviate injury. MATERIALS AND METHODS: The abdominal aorta of male Sprague Dawley (SD) rats or C57BL/6 J mice was clamped sequentially throughout its length. Transforming growth factor ß1 (TGFß1), SB431542, lipopolysaccharide (LPS), Necrostatin-1 (Nec-1), rapamycin, or MHY1485 contained in Pluronic gel was injected intramurally at day 0 or day 7. Animals were fed with chow containing 0.25% beta-aminopropionitrile (BAPN) to evaluate the influence of BAPN. All samples were harvested and examined by immunohistochemistry and immunofluorescence. RESULTS: The clamped rat aorta showed luminal dilation, elastin fiber breaks, neointimal hyperplasia, and dissection (days 0-90). Intramural injection of TGFß1, rapamycin and Nec-1 showed a protective effect on the injured aorta, whereas SB431542, MHY1485 and LPS showed more severe wall damage. The aortic lumen in rats fed with BAPN was significantly larger than in control rats (day 7). Mouse aorta showed similar injury with neointimal hyperplasia and elastin fiber breaks. CONCLUSIONS: The rodent arterial injury model is reproducible and may mimic early changes of arterial injury. The model accommodates intramural injection of different drugs that may show mechanisms of arterial injury. Although this is a preliminary animal model, the intramural injection method may have potential clinical application in the future.

A Systematic Review and Meta-Analysis of Seasonal and Monthly Variability in the Incidence of Acute Aortic Dissection.

BACKGROUND: This study explored seasonal and monthly variations of the incidence of acute aortic dissection (AAD). METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched up to July 2021. Temporal variation in the incidence of AAD was analyzed including all studies analyzing seasonal and monthly aggregations. Then, we performed subgroup analyses according to the type of AAD. Two authors independently reviewed and extracted data. RESULTS: Twenty-seven studies for a total of 128,101 patients were included. Our results showed that the incidence of AAD was highest in winter and lowest in summer. Regardless of type A or type B, the incidence of AAD was significantly higher in winter than in summer and autumn. Nonetheless, there was no significant difference between spring and winter, and between summer and autumn. Results may be limited by the quality of the included articles. However, in the sensitivity analysis that excluded low-quality studies, results did not change significantly. In addition, the pooled incidence was highest in January and lowest in August. CONCLUSIONS: Our data strongly support the presence of distribution patterns in the incidence of AAD, characterized by significantly higher risk in winter and in January. These distribution patterns of AAD incidence may help to develop better prevention strategies.

Egg Shell Membrane as an Alternative Vascular Patch for Arterial Angioplasty.

Introduction: The egg shell membrane (ESM) is always considered as waste, but recent studies have shown that it has the potential to yield rapid re-endothelialization in vitro. We hypothesized that ESM and heparin-conjugated ESM (HESM) can be used as arterial patch in a rat aortic angioplasty model. Method: Sprague-Dawley rat (200 g) abdominal aortic patch angioplasty model was used. Decellularized rat thoracic aorta (TA) patch was used as the control; ESM patch was made of raw chicken egg; heparin-coated ESM (HESM) patch was made by using dopamine; anticoagulation properties were verified using platelet adhesion tests; the TA, ESM, and HESM patches were implanted to the rat aorta and harvested at day 14; and the samples were examined by immunohistochemistry and immunofluorescence. Result: The ESM patch showed a similar healing process to the TA patch; the cells could migrate and infiltrate into both patches; there was a neointima with von Willebrand factor-positive endothelial cells; the endothelial cells acquired arterial identity with Ephrin-B2- and dll-4-positive cells; there were proliferating cell nuclear antigen (PCNA)-positive cells, and PCNA and alpha smooth muscle actin dual-positive cells in the neointima in both groups. Heparin was conjugated to the patch successfully and showed a strong anticoagulation property in vitro. HESM could decrease mural thrombus formation after rat aortic patch angioplasty. Conclusion: The ESM is a natural scaffold that can be used as a vascular patch; it showed a similar healing process to decellularized TA patch; HESM showed anticoagulation property both in vitro and in vivo; and the ESM may be a promising vascular graft in the clinic.

Adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle inhibits neointimal hyperplasia in a rat aortic wire injury model.

Neointimal hyperplasia is a persistent complication after vascular interventions, and it is also the leading cause of vascular graft restenosis and failure after arterial interventions, so novel treatment methods are needed to treat this complication. We hypothesized that adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle (hydrogel-PLGA-rapamycin) could inhibit neointimal hyperplasia in a rat aortic wire injury model. The HA/SA hydrogel was fabricated by the interaction of hyaluronic acid (HA), sodium alginate (SA), and CaCO3; and loaded with PLGA rapamycin nanoparticle or rhodamine uniformly. A SD rat aortic wire injury induced neointimal hyperplasia model was developed, the control group only received wire injury, the adventitial application group received 10 µL hydrogel-PLGA-rapamycin after wire injury, and the adventitial injection group received 10 µL hydrogel-PLGA-rapamycin injected into the aortic adventitia after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with rhodamine can be successfully injected into the aortic adventitia and was encapsuled by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection but was almost degraded at day 21. There was a significantly thinner neointima in the adventitial application group and adventitial injection group compared to the control group (p = 0.0009). There were also significantly fewer CD68+ (macrophages) cells (p = 0.0012), CD3+ (lymphocytes) cells (p = 0.0011), p-mTOR+ cells (p = 0.0019), PCNA+ cells (p = 0.0028) in the adventitial application and adventitial injection groups compared to the control group. The endothelial cells expressed arterial identity markers (Ephrin-B2 and dll-4) in all these three groups. Adventitial injection of hydrogel-PLGA-rapamycin can effectively inhibit neointimal hyperplasia after rat aortic wire injury. This may be a promising drug delivery method and therapeutic choice to inhibit neointimal hyperplasia after vascular interventions.

PLGA Nanoparticle Rapamycin- or Necrostatin-1-Coated Sutures Inhibit Inflammatory Reactions after Arterial Closure in Rats.

Background: The inflammatory reaction of sutures and oozing after arterial closure depends on the suture material and the amount of oozing surrounding the sutures. Anti-inflammation coatings have been proven to be an effective strategy to decrease this reaction. The aim of this study was to establish an arterial closure oozing model in rats and to test the effect of poly (lactic-co-glycolic acid) (PLGA) nanoparticle (NP) rapamycin- or necrostatin-1(NEC-1)-coated sutures on the inflammatory reaction after arterial closure. Methods and Materials: A 10 mm arteriotomy was carried out on the carotid artery of Sprague-Dawley rats and closed using 11-0 sutures. PLGA NP-rapamycin and NEC-1 were made. The 11/0 nylon sutures were coated with PLGA NP-rapamycin and NEC-1. Sutures were examined by scanning electron microscopy, hemolysis test, and cumulative release. The carotid arteriotomy was closed using uncoated PLGA NP-rapamycin- and NP-NEC-1-coated sutures. The carotid artery was harvested on day 7. Tissues were examined by histology and immunohistochemistry. Results: There were severe inflammatory reactions in the oozing arteries compared to the normal healing arteries (P = 0.0192). PLGA NP-rapamycin- and NEC -1-coated sutures reduced foreign body reaction compared to the uncoated sutures. There were significantly smaller number of CD3 (P = 0.0068), CD45 (P = 0.0300), and CD68 (P = 0.0011) cells in the PLGA NP-rapamycin- and NP-NEC-1-coated groups compared to the uncoated group. There was a smaller number of p-mTOR (P = 0.0198)-positive cells in the PLGA NP-rapamycin-coated group compared to the uncoated group. There was a smaller number of TNFα (P = 0.0198)-positive cells in the PLGA NP-NEC-1-coated group compared to the uncoated group. Conclusions: In this rat carotid artery oozing model, PLGA NP-rapamycin- or NP-NEC-1-coated sutures can inhibit inflammatory reaction and foreign body reaction. Although this was a small rodent animal experiment, this coated suture may have a potential clinical application in the future.

Biodegraded PCl and gelatin fabricated vascular patch in rat aortic and inferior vena cava angioplasty.

Novel synthetic prosthesis materials for patch angioplasty are continuously under development and optimization. When a nonwoven-based gelatin membrane is coupled with an electrospun layer of polycaprolactone (PCL), these biohybrid polymer membranes (BHMs) possess higher mechanical properties in aqueous environments. We hypothesized that BHMs can also be used as vascular patches, and we tested our hypothesis in a rat IVC venoplasty and aortic arterioplasty model. Patch venoplasty and arterioplasty were performed in SD rats (200 g), the patches were harvested at day 14, and samples were analyzed by immunohistochemistry and immunofluorescence. The BHM patches were almost degraded, with few parts remaining after 14 days. There was a line of CD34- and nestin-positive cells on the endothelium, with some cells were CD34 and nestin dual-positive, macrophages and leukocytes also participated in the patch healing process. There were PCNA-positive cells in the neointima and peri-patch area, with some cells were also PCNA and α-actin dual-positive. Arterial neointimal endothelial cells were Ephrin-B2- and dll-4-positive, and venous neointimal endothelial cells were Eph-B4- and COUP-TFII-positive. BHM shares a similar healing process like other patch materials, and BHM may have potential applications in vascular surgery.

Early Outcomes of Complex Vascular Reconstructions in Lower Extremities Using Spiral and Panel Vein Grafts.

BACKGROUND: Spiral saphenous vein grafts (SSVG) or paneled vein grafts (PVG) can be used when the diameter of the autologous great saphenous vein does not match the vessel that needs to be repaired. This study aimed to present early results of complex vascular reconstruction with SSVGs and PVGs in the lower extremities. METHODS: From May 2019 through January 2021, 6 SSVGs and 3 PVGs were used for vascular reconstruction in 9 patients. Patient data were collected retrospectively, including age, gender, cause of vascular pathology, target vessels, concomitant injury, surgical method, additional surgical methods, and hemodynamic status. The Kaplan-Meier method was used to calculate the rate of freedom from reintervention. RESULTS: Among these patients, 7 had trauma, 1 had graft infection, and 1 had vascular reconstruction after tumor excision. The mean duration of follow-up was 6 ± 6.6 months (range 1-19 months). The rate of freedom from reintervention for any reason was 77.8% at 1 year. Two patients underwent amputation after vascular reconstruction with patent vascular reconstructions. One of the 2 amputations was performed because of infection, and the other was due to ischemia >24 hr. The success rate of reconstruction was 100%, and the primary patency rate was 100%. The rate of limb salvage was 77.8%. There was no death, bleeding, embolism, skin ulcers, graft-related complication, or aneurysmal dilation during follow-up. CONCLUSIONS: SSVG and PVG were associated with low infection rates and satisfactory short-term patency rates. Both 2 grafts may be good choices when there is a diameter mismatch in vascular reconstructions.

Endothelial nitric oxide synthase (eNOS) mediates neointimal thickness in arteriovenous fistulae with different anastomotic angles in rats.

BACKGROUND: It is known that the anastomotic angle can influence neointimal hyperplasia and patency in arteriovenous fistulae (AVF). Endothelial nitric oxide synthase (eNOS) is released from the vascular endothelium and can inhibit neointimal hyperplasia. Therefore, here, we aimed to test the hypothesis that the manipulation of eNOS expression could influence neointimal thickness in a rat AVF model with different anastomosis angles. METHODS: Rat carotid artery (inflow, CA) and jugular vein (outflow, JV) AVF were created with acute, blunt, or end-to-end (ETE) anastomosis angles. Aspirin was used to increase eNOS expression in the acute angle group, while N(G)-nitro-L-arginine methyl ester (L-name) was used to decrease eNOS expression in the obtuse angle group. The rats were sacrificed on day 21, and tissues were harvested and analyzed histologically and with immunostaining. RESULTS: A larger anastomosis diameter (p < 0.016) and smaller neointimal area (p < 0.01) were observed in the obtuse and end-to-end (ETE) groups compared to in the acute group. In the acute angle group, there were more proliferating cell nuclear antigen (PCNA) and α-actin dual-positive cells (p < 0.0001) and fewer phospho (p)-eNOS-positive endothelial cells (p < 0.0001) in the neointima than in the obtuse and ETE angle groups. On treating the acute angle and blunt angle groups with aspirin and L-name, respectively, no significant differences in the neointima/lumen rate were observed (p = 0.6526) between the groups; however, there were fewer von Willebrand factor (vWF) and p-eNOS dual-positive cells in the obtuse angle group treated with L-name (p = 0.0045). CONCLUSIONS: We demonstrated that eNOS plays an important role in neointimal hyperplasia in AVF with different anastomosis angles; further, eNOS could potentially be used as a therapeutic target in patients with AVF in the future.

A Novel Plant Leaf Patch Absorbed With IL-33 Antibody Decreases Venous Neointimal hyperplasia.

Introduction: We recently showed that a decellularized leaf scaffold can be loaded with polylactic-co-glycolic acid (PLGA)-based rapamycin nanoparticles, this leaf patch can then inhibit venous neointimal hyperplasia in a rat inferior vena cava (IVC) venoplasty model. IL-33 plays a role in the neointimal formation after vascular injury. We hypothesized that plant leaves can absorb therapeutic drug solution and can be used as a patch with drug delivery capability, and plant leaves absorbed with IL-33 antibody can decrease venous neointimal hyperplasia in the rat IVC venoplasty model. Method: A human spiral saphenous vein (SVG) graft implanted in the popliteal vein was harvested from a patient with trauma and analyzed by immunofluorescence. Male Sprague-Dawley rats (aged 6-8 weeks) were used to create the IVC patch venoplasty model. Plant leaves absorbed with rhodamine, distilled water (control), rapamycin, IL-33, and IL-33 antibody were cut into patches (3 × 1.5 mm2) and implanted into the rat IVC. Patches were explanted at day 14 for analysis. Result: At day 14, in the patch absorbed with rhodamine group, immunofluorescence showed rhodamine fluorescence in the neointima, inside the patch, and in the adventitia. There was a significantly thinner neointima in the plant patch absorbed with rapamycin (p = 0.0231) compared to the patch absorbed with distilled water. There was a significantly large number of IL-33 (p = 0.006) and IL-1ß (p = 0.012) positive cells in the human SVG neointima compared to the human great saphenous vein. In rats, there was a significantly thinner neointima, a smaller number of IL-33 (p = 0.0006) and IL-1ß (p = 0.0008) positive cells in the IL-33 antibody-absorbed patch group compared to the IL-33-absorbed patch group. Conclusion: We found that the natural absorption capability of plant leaves means they can absorb drug solution efficiently and can also be used as a novel drug delivery system and venous patch. IL-33 plays a role in venous neointimal hyperplasia both in humans and rats; neutralization of IL-33 by IL-33 antibody can be a therapeutic method to decrease venous neointimal hyperplasia.

The application of tissue-engineered fish swim bladder vascular graft.

Small diameter (< 6 mm) prosthetic vascular grafts continue to show very low long-term patency, but bioengineered vascular grafts show promising results in preclinical experiments. To assess a new scaffold source, we tested the use of decellularized fish swim bladder as a vascular patch and tube in rats. Fresh goldfish (Carassius auratus) swim bladder was decellularized, coated with rapamycin and then formed into patches or tubes for implantation in vivo. The rapamycin-coated patches showed decreased neointimal thickness in both the aorta and inferior vena cava patch angioplasty models. Rapamycin-coated decellularized swim bladder tubes implanted into the aorta showed decreased neointimal thickness compared to uncoated tubes, as well as fewer macrophages. These data show that the fish swim bladder can be used as a scaffold source for tissue-engineering vascular patches or vessels.

Biomimetic Elastin Fiber Patch in Rat Aorta Angioplasty.

Introduction: Vascular grafts significantly contribute to advances in vascular surgery, but none of the currently available prosthetic grafts have elastin fibers similar to native arteries. We hypothesized that a novel elastin patch could be produced after a rat decellularized thoracic aorta elastin fiber scaffold is implanted subcutaneously in rats; we tested this novel elastin patch in a rat aortic arterioplasty model. Methods: Sprague-Dawley rats (200 g) were used. Rat thoracic aortae were decellularized and sectioned at a thickness of 30 µm. A single elastin fiber scaffold was fabricated as a net (5 × 5 mm2), and then a three-layer scaffold was constructed to make a new patch. The hyaluronic acid-sodium alginate (HA/SA) hydrogel was fabricated by reacting sodium SA, HA, and CaCO3, and then the hydrogel was added to the patch to secure the elastin fibers. The patches were implanted subcutaneously in rats and harvested at day 14. The elastin patches were then implanted into the same rat's aorta and harvested at day 14; a decellularized rat thoracic aorta (TA) patch was used as a control. Sections of the retrieved patches were stained by immunohistochemistry and immunofluorescence. Results: The elastin fibers could be secured by the hydrogel. After 14 days, the subcutaneously implanted elastin patch was incorporated into the rat tissue, and H&E staining showed that new tissue had formed around the elastin patch with almost no hydrogel left. After implantation into the rat aorta and then retrieval on day 14, H&E staining showed that there was neointima and adventitia formation in both the TA and elastin patch groups. Both patches showed a similar histological structure after implantation, and immunofluorescence showed that there were CD34- and nestin-positive cells in the neointima. In both groups, the endothelial cells expressed the arterial identity markers Ephrin-B2 and dll-4; almost one-third of the cells in the neointima were PCNA-positive with rare cleaved caspase-3-positive cells. Conclusion: We demonstrated a novel approach to making elastin fiber scaffold hydrogel patches (elastin patches) and tested them in a rat aorta arterioplasty model. This patch showed a similar healing process as the decellularized TA patch; it also showed potential applications in large animals and may be a substitute for prosthetic grafts in vascular surgery.

Hydrogel-coated needles prevent puncture site bleeding in arteriovenous fistula and arteriovenous grafts in rats.

INTRODUCTION: Imperfect hemostasis after arteriovenous fistula (AVF) and arteriovenous graft (AVG) cannulation can cause a hematoma or pseudoaneurysm and leads to poor satisfaction. We hypothesized that a hydrogel-coated needle would effectively and rapidly stop bleeding after vascular cannulation in a rat AVF and AVG model. METHOD: A hydrogel comprised of sodium alginate (SA), hyaluronic acid (HA), and calcium carbonate was coated onto the surface of suture needles using a rotating system. The needles were observed using scanning electron microscopy (SEM) and immunofluorescence. Rat AVF with or without renal failure and AVG were punctured using bare and hydrogel-coated needles. The tissues were examined by histology. RESULT: The hydrogel was successfully coated onto the surface of 30 G needles and confirmed by SEM. Hydrogel-coated needles rapidly stopped bleeding after AVF and AVG cannulation in rat. CONCLUSION: In this preliminary animal research, hydrogel-coated needles can stop AVF and AVG puncture-site bleeding; but additional clinical studies are needed to justify whether it is still effective in clinical.

Immune checkpoint programmed death-1 mediates abdominal aortic aneurysm and pseudoaneurysm progression.

PURPOSE: The causes and pathogenetic mechanisms underlying abdominal aortic aneurysms (AAAs) and pseudoaneurysms are not fully understood. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease AAA and pseudoaneurysm formation in mouse and rat models. METHODS: Human AAA samples were examined in conjunction with an adventitial calcium chloride (CaCl2) application mouse model and an aortic patch angioplasty rat model. Single-dose PD-1 antibody (4 mg/kg) or BMS-1 (PD-1 inhibitor-1) (1 mg/kg) was administered by intraperitoneal (IP) or intraluminal injection. In the intramural injection group, PD-1 antibody was injected after CaCl2 incubation. The rats were divided into three groups: (1) the control group was only decellularized without other special treatment, (2) the PD-1 antibody-coated patch group, and (3) the BMS-1 coated patch group. Patches implanted in the rat abdominal aorta were harvested on day 14 after implantation and analyzed. RESULTS: Immunohistochemical analysis showed PD-1-positive cells, PD-1 and CD3, PD-1 and CD68, and PD-1 and α-actin co-expressed in the human AAA samples. Intraperitoneal (IP) injection or intraluminal injection of PD-1antibody/BMS-1 significantly inhibited AAA progression. PD-1 antibody and BMS-1 were each successfully conjugated to decellularized rat thoracic artery patches, respectively, by hyaluronic acid. Patches coated with either humanized PD-1 antibody or BMS-1 can also inhibit pseudoaneurysm progression and inflammatory cell infiltration. CONCLUSION: PD-1 pathway inhibition may be a promising therapeutic strategy for inhibiting AAA and pseudoaneurysm progression.

Programmed death-1 mediates venous neointimal hyperplasia in humans and rats.

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.

Application of the Tissue-Engineered Plant Scaffold as a Vascular Patch.

Tissue-engineered plant scaffolds have shown promising applications in in vitro studies. To assess the applicability of natural plant scaffolds as vascular patches, we tested decellularized leaf and onion cellulose in a rat inferior vena cava patch venoplasty model. The leaf was decellularized, and the scaffold was loaded with polylactic-co-glycolic acid (PLGA)-based rapamycin nanoparticles (nanoparticles). Nanoparticle-perfused leaves showed decreased neointimal thickness after implantation on day 14; there were also fewer CD68-positive cells and PCNA-positive cells in the neointima in the nanoparticle-perfused patches than in the control patches. Onion cellulose was decellularized, coated with rapamycin nanoparticles, and implanted in the rat; the nanoparticle-coated onion cellulose patches also showed decreased neointimal thickness. These data show that natural plant-based scaffolds may be used as novel scaffolds for tissue-engineered vascular patches. However, further modifications are needed to enhance patch strength for artery implantations.