Novel Multifunctional Nanomatrix Reduces Inflammation in Dynamic Conditions in Vitro and Dilates Arteries ex Vivo

Alexander, Grant C.,Vines, Jeremy B.,Hwang, Patrick,Kim, Teayoun,Kim, Jeong-a,Brott, Brigitta C.,Yoon, Young-Sup,Jun, Ho-Wook American Chemical Society 2016 ACS APPLIED MATERIALS & INTERFACES Vol.8 No.8

<P>Inflammatory responses play a critical role in tissue implant interactions, often limiting current implant utility. This is particularly true for cardiovascular devices. Existing stent technology does little to avoid or mitigate inflammation or to influence the vasomotion of the artery after implantation. We have developed a novel endothelium-mimicking nanomatrix composed of peptide amphiphiles that enhances endothelialization while decreasing both smooth muscle cell proliferation and platelet adhesion. Here, we evaluated whether the nanomatrix could prevent inflammatory responses under static and physiological flow conditions. We found that the nanomatrix reduced monocyte adhesion to endothelial cells and expression of monocyte inflammatory genes (TNF-alpha, MCP-1, IL-1 beta, and IL-6). Furthermore, the nitric-oxide releasing nanomatrix dramatically attenuated TNF-alpha-stimulated inflammatory responses as demonstrated by significantly reduced monocyte adhesion and inflammatory gene expression in both static and physiological flow conditions. These effects were abolished by addition of a nitric oxide scavenger. Finally, the nanomatrix stimulated vasodilation in intact rat mesenteric arterioles after constriction with phenylephrine, demonstrating the bioavailability and bioactivity of the nanomatrix, as well as exhibiting highly desired release kinetics. These results demonstrate the clinical potential of this nanomatrix by both preventing inflammatory responses and promoting vasodilation, critical improvements in stent and cardiovascular device technology.</P>

Rotator cuff repair: what questions are patients asking online and where are they getting their answers?

Alexander J. Hodakowski,Johnathon R. McCormick,Dhanur Damodar,Matthew R. Cohn,Kyle D. Carey,Nikhil N. Verma,Gregory Nicholson,Grant E Garrigues 대한견주관절학회 2023 대한견주관절의학회지 Vol.26 No.1

Background: This study analyzed questions entered online by rotator cuff patients and determined types and quality of websites providing information at the top of queries. Methods: Three strings related to rotator cuff repair were explored in Google Search. The result pages were manually collected under the “People also ask” function for frequent questions and associated webpages. Questions were categorized using Rothwell’s classification with further topical subcategorization. Webpages were evaluated by Journal of American Medical Association (JAMA) benchmark criteria for source quality. Results: One hundred twenty “People also ask” questions were collected with their associated webpages. Based on the Rothwell classification of questions, queries were thematically organized into fact (41.7%), value (31.7%), and policy (26.7%) categories. The most common webpage categories were academic (28.3%) and medical practice (27.5%). The most common question subcategories were timeline of recovery (21.7%), indications/management (21.7%), and pain (18.3%). The average JAMA score for all 120 webpages was 1.50. Journal articles had the highest average JAMA score (3.77), while commercial websites had the lowest JAMA score (0.91). The most common suggested question for rotator cuff repair/surgery was, “Is rotator cuff surgery worth having?,” while the most common suggested question for rotator cuff repair pain was, “What happens if a rotator cuff is not repaired?” Conclusions: The most common questions asked on Google pertaining to rotator cuff repair evaluate management options and relate to the timeline of recovery and pain management. Most information is provided by medical practice, academic, and medical information websites, which have highly variable reliability. By understanding the questions that rotator cuff repair patients are asking online, surgeons can tailor preoperative education to common patient concerns and improve postoperative outcomes. Level of evidence: IV.

Remote handling systems for the ISAC and ARIEL high-power fission and spallation ISOL target facilities at TRIUMF

Minor, Grant,Kapalka, Jason,Fisher, Chad,Paley, William,Chen, Kevin,Kinakin, Maxim,Earle, Isaac,Moss, Bevan,Bricault, Pierre,Gottberg, Alexander Korean Nuclear Society 2021 Nuclear Engineering and Technology Vol.53 No.4

TRIUMF, Canada's particle accelerator centre, is constructing a new high-power ISOL (Isotope Separation On-Line) facility called ARIEL (Advanced Rare IsotopE Laboratory). Thick porous targets will be bombarded with up to 48 kW of 480 MeV protons from TRIUMF's cyclotron, or up to 100 kW of 30 MeV electrons from a new e-linac, to produce short-lived radioisotopes for a variety of applications, including nuclear astrophysics, fundamental nuclear structure and nuclear medicine. For efficient release of radioisotopes, the targets are heated to temperatures approaching 2000 ℃, and are exposed to GSv/h level radiation fields resulting from intended fissions and spallations. Due to these conditions, the operational life for each target is only about five weeks, calling for frequent remote target exchanges to limit downtime. A few days after irradiation, the targets have a residual radiation field producing a dose rate on the order of 10 Sv/h at 1 m, requiring several years of decay prior to shipment to a national disposal facility. TRIUMF is installing new remote handling infrastructure dedicated to ARIEL, including hot cells and a remote handling crane. The system design applies learnings from multiple existing facilities, including CERN-ISOLDE, GANIL-SPIRAL II as well as TRIUMF's ISAC (Isotope Separator and ACcelerator).

Biomimetic Prohealing Nanomatrix for Stent and Atherosclerosis Model

Xixi Zhang,Jun Chen,Grant C. Alexander,Patrick TJ. Hwang,Peter G. Anderson,Young-Sup Yoon,Brigitta C. Brott,Ho-Wook Jun(전호욱) 한국고분자학회 2021 한국고분자학회 학술대회 연구논문 초록집 Vol.46 No.1

Topic 1 for Stent coating: Cardiovascular disease is the number one cause of death worldwide. Stents are the most commonly implanted devices to effectively treat cardiovascular disease. However, bare metal stent (BMS) remains limited by relatively high rates of in-stent restenosis and the accompanying extracellular matrix deposition. Thus, drug-eluting stents (DES) have been developed to reduce restenosis. Although these efforts were successful, DES has its own set of shortcomings: late stent thrombosis, inflammation and delayed re-endothelialization. To address these issues, we developed a novel prohealing multifunctional stent coating: a nitric oxide (NO)-releasing endothelium-mimicking nanomatrix composed of the biomaterial- Peptide Amphiphile (PA). We evaluated the safety and efficacy of the novel coated stent in the rabbit iliac artery balloon injury model and compared with commercially available BMS and DES. The goal is to demonstrate the advantages of the nanomatrix coating which could enhance re-endothelialization, while reduce restenosis, inflammation, and thrombosis. We hypothesize that the prohealing multifunctional nanomatrix coated stent has several strengths compared with BMS and DES: 1) promoted re-endothelialization; 2) less restenosis than BMS; and 3) less inflammation and thrombosis than DES. Topic 2 for atherosclerosis model: Atherosclerosis is the main cause of cardiovascular disease. To evaluate therapeutics for treating atherosclerosis, in vivo and in vitro atherosclerosis models are developed. However, those atherosclerosis models have their own limitations. In vivo models, like pig and non-human primates, can develop lesions in coronary arteries, however, inducing atherosclerosis in them requires high cholesterol intake, long induction time, gene knock-out, and high expense. Although mouse models are the predominant models used in the labs, however, most of the currently mouse models show different plaque structure and genome from that of human. In vitro models are also used for evaluation due to their low cost; however, most of the those models are not generated following the pathogenesis of human atherosclerosis and are two-dimensional (2D) models which are limited to static culture in tissue culture plate and unable to provide three-dimensional (3D) tissue structures with proper functions. Thus, the main goal of this proposal is to develop an innovative biologically inspired 3D in vitro platform – tissue engineered atherosclerosis model (TEAM), featured with endothelial dysfunction, macrophages, and foam cells, following the pathogenesis of human atherosclerosis with low cost.

Adult stem cells and tissue engineering strategies for salivary gland regeneration: a review

Chankee Yoo,Jeremy B Vines,Grant Alexander,Kyle Murdock,Patrick Hwang,Ho-Wook Jun 한국생체재료학회 2014 생체재료학회지 Vol.18 No.3

Saliva is an important compound produced by the salivary glands and performs numerous functions. Hyposalivation (dry mouth syndrome) is a deleterious condition often resulting from radiotherapy for patients with head and neck cancer, Sjogren’s Syndrome, or as a side effect of certain medications. Hyposalivation negatively affects speaking, mastication, and swallowing in afflicted patients, greatly reducing their quality of life. Current treatments for this pathology include modifying lifestyle, synthetic saliva supplementation, and the utilization of salivary gland stimulants and sialagogues. However, many of these treatments do not address the underlying issues and others are pervaded by numerous side effects. In order to address the shortcomings related to current treatment modalities, many groups have diverted their attention to utilizing tissue engineering and regenerative medicine approaches. Tissue engineering is defined as the application of life sciences and materials engineering toward the development of tissue substitutes that are capable of mimicking the structure and function of their natural analogues within the body. The general underlying strategy behind the development of tissue engineered organ substitutes is the utilization of a combination of cells, biomaterials, and biochemical cues intended to recreate the natural organ environment. The purpose of this review is to highlight current bioengineering approaches for salivary gland tissue engineering and the adult stem cell sources used for this purpose. Additionally, future considerations in regard to salivary gland tissue engineering strategies are discussed.

Evaluation of ciprofloxacin and metronidazole encapsulated biomimetic nanomatrix gel on Enterococcus faecalis and Treponema denticola

Sagar N Kaushik,Jessica Scoffield,Adinarayana Andukuri,Grant C Alexander,Taneidra Walker,김석곤,최성철,Brigitta C Brott,Paul D Eleazer,이진용,Hui Wu,Noel K Childers,Ho-Wook Jun,박재홍,Kyounga Cheon 한국생체재료학회 2015 생체재료학회지 Vol.19 No.2

Background: A triple antibiotic mixture (ciprofloxacin; CF, metronidazole; MN, and minocycline; MC) has been used for dental root canal medicaments in pulp regeneration therapy. However, tooth discolorations, cervical root fractures, and inadequate pulp-dentin formation have been reported due to the triple antibiotic regimen. Therefore, an antibiotic encapsulated biomimetic nanomatrix gel was developed to minimize the clinical limitations and maximize a natural healing process in root canal infections. In this study, minimal bacterial concentrations (MBC) of the selected antibiotics (CF and MN) were tested in 14 representative endodontic bacterial species. Then MBC of each CF and MN were separately encapsulated within the injectable self-assembled biomimetic nanomatrix gel to evaluate antibacterial level on Enterococcus faecalis and Treponema denticola. Results: Antibiotic concentrations lower than 0.2 μg/mL of CF and MN demonstrated antibacterial activity on the 14 endodontic species. Furthermore, 6 different concentrations of CF and MN separately encapsulated with the injectable self-assembled biomimetic nanomatrix gel demonstrated antibacterial activity on Enterococcus faecalis and Treponema denticola at the lowest tested concentration of 0.0625 μg/mL. Conclusions: These results suggest that each CF and MN encapsulated within the injectable self-assembled biomimetic nanomatrix gel demonstrated antibacterial effects, which could be effective for the root canal disinfection while eliminating MC. In the long term, the antibiotic encapsulated injectable self-assembled biomimetic nanomatrix gel can provide a multifunctional antibiotic delivery method with potential root regeneration. Further studies are currently underway to evaluate the effects of combined CF and MN encapsulated within the injectable self-assembled biomimetic nanomatrix gel on clinical samples.

Evaluation of the effect of expansion and shear stress on a self-assembled endothelium mimicking nanomatrix coating for drug eluting stents <i>in vitro</i> and <i>in vivo</i>

Andukuri, Adinarayana,Min, IlJae,Hwang, Patrick,Alexander, Grant,Marshall, Lauren E,Berry, Joel L,Wick, Timothy M,Joung, Yoon Ki,Yoon, Young-Sup,Brott, Brigitta C,Han, Dong Keun,Jun, Ho-Wook IOP Publishing 2014 Biofabrication Vol.6 No.3

<P>Coating stability is increasingly recognized as a concern impacting the long-term effectiveness of drug eluting stents (DES). In particular, unstable coatings have been brought into focus by a recently published report (Denardo et al 2012 J. Am. Med. Assoc. 307 2148-50). Towards the goal of overcoming current challenges of DES performance, we have developed an endothelium mimicking nanomatrix coating composed of peptide amphiphiles that promote endothelialization, but limit smooth muscle cell proliferation and platelet adhesion. Here, we report a novel water evaporation based method to uniformly coat the endothelium mimicking nanomatrix onto stents using a rotational coating technique, thereby eliminating residual chemicals and organic solvents, and allowing easy application to even bioabsorbable stents. Furthermore, the stability of the endothelium mimicking nanomatrix was analyzed after force experienced during expansion and shear stress under simulated physiological conditions. Results demonstrate uniformity and structural integrity of the nanomatrix coating. Preliminary animal studies in a rabbit model showed no flaking or peeling, and limited neointimal formation or restenosis. Therefore, it has the potential to improve the clinical performance of DES by providing multifunctional endothelium mimicking characteristics with structural integrity on stent surfaces.</P>

Progress and challenges of the bioartificial pancreas

Hwang Patrick T. J.,Shah Dishant K.,Garcia Jacob A.,Bae Chae Yun,Lim Dong-Jin,Huiszoon Ryan C.,Alexander Grant C.,Jun Ho-Wook 나노기술연구협의회 2016 Nano Convergence Vol.3 No.28

Pancreatic islet transplantation has been validated as a treatment for type 1 diabetes since it maintains consistent and sustained type 1 diabetes reversal. However, one of the major challenges in pancreatic islet transplantation is the body’s natural immune response to the implanted islets. Immunosuppressive drug treatment is the most popular immunomodulatory approach for islet graft survival. However, administration of immunosuppressive drugs gives rise to negative side effects, and long-term effects are not clearly understood. A bioartificial pancreas is a therapeutic approach to enable pancreatic islet transplantation without or with minimal immune suppression. The bioartificial pancreas encapsulates the pancreatic islets in a semi-permeable environment which protects islets from the body’s immune responses, while allowing the permeation of insulin, oxygen, nutrients, and waste. Many groups have developed various types of the bioartificial pancreas and tested their efficacy in animal models. However, the clinical application of the bioartificial pancreas still requires further investigation. In this review, we discuss several types of bioartificial pancreases and address their advantages and limitations. We also discuss recent advances in bioartificial pancreas applications with microfluidic or micropatterning technology.