Synergistic effect of Hypoxic Conditioning and Cell-Tethering Colloidal Gels enhanced Productivity of MSC Paracrine Factors and Accelerated Vessel Regeneration.

Microporous hydrogels have been widely used for delivering therapeutic cells. However, several critical issues, such as the lack of control over the harsh environment they are subjected to under pathological conditions and rapid egression of cells from the hydrogels, have produced limited therapeutic outcomes. To address these critical challenges, cell-tethering and hypoxic conditioning colloidal hydrogels containing mesenchymal stem cells (MSCs) are introduced to increase the productivity of paracrine factors locally and in a long-term manner. Cell-tethering colloidal hydrogels that are composed of tyramine-conjugated gelatin prevent cells from egressing through on-cell oxidative phenolic crosslinks while providing mechanical stimulation and interconnected microporous networks to allow for host-implant interactions. Oxygenating microparticles encapsulated in tyramine-conjugated colloidal microgels continuously generated oxygen for 2 weeks with rapid diffusion, resulting in maintaining a mild hypoxic condition while MSCs consumed oxygen under severe hypoxia. Synergistically, local retention of MSCs within the mild hypoxic-conditioned and mechanically robust colloidal hydrogels significantly increased the secretion of various angiogenic cytokines and chemokines. The oxygenating colloidal hydrogels induced anti-inflammatory responses, reduced cellular apoptosis, and promoted numerous large blood vessels in vivo. Finally, mice injected with the MSC-tethered oxygenating colloidal hydrogels significantly improved blood flow restoration and muscle regeneration in a hindlimb ischemia (HLI) model.

Development and Feasibility Evaluation of Smart Cancer Care 2.0 Based on Patient-Reported Outcomes for Post-Discharge Management of Patients with Cancer.

PURPOSE: A "Smart Cancer Care" platform that integrates patient-reported outcomes (PROs) with management has been established in Korea. This study focused on improving health behaviors and connecting patients to welfare services by introducing and assessing the feasibility of "Smart Cancer Care 2.0," an enhanced version designed for monitoring complications post-cancer treatment. MATERIALS AND METHODS: Smart Cancer Care 2.0 was developed by conducting a literature review and consulting with expert panels to identify symptoms or variables requiring monitoring and management guidelines based on the treatment type. Qualitative and quantitative surveys were conducted to assess the feasibility of the app and web system based on the experiences of patients with cancer and healthcare workers. RESULTS: A total of 81 symptoms or variables (chemotherapy-, surgery-, radiotherapy-, rehabilitation-, and health management-related) were selected for management in Smart Cancer Care 2.0. PROs for these symptoms were basically categorized into three severity grades: preventive management, self-treatment, and consultation with a healthcare worker or visit to a healthcare institution. The overall mean scores in the feasibility evaluation by patients and healthcare workers were 3.83 and 3.90 points, respectively, indicating high usefulness. CONCLUSION: Smart Cancer Care 2.0 leverages the existing information and communication technologies-based platform, Smart Cancer Care, and further includes health behaviors and welfare services. Smart Cancer Care 2.0 may play a crucial role in establishing a comprehensive post-discharge management system for patients with cancer as it provides suitable interventions based on patients' responses and allows the regularly collected PROs to be easily viewed for streamlined care.

4D-printed microneedles from dual-sensitive chitosan for non-transdermal drug delivery.

Microneedles are a promising micro-scale drug delivery platform that has been under development for over two decades. While 3D printing technology has been applied to fabricate these systems, the challenge of achieving needle sharpness remains. In this study, we present an innovative approach for microneedle fabrication using digital light processing (DLP) 3D printing and smart chitosan biomaterial. For the first time, we used hydroxybutyl methacrylated chitosan (HBCMA), which possesses dual temperature- and photo-sensitive properties, to create microneedles. The DLP approach enabled a quick generation of HBCMA-based microneedles with a high resolution. The microneedles exhibited 4D properties with a change in needle dimensions upon exposure to temperature, which enhances resolution, sharpens needles, and improves mechanical strength. We demonstrated the ability of these microneedles to load, deliver, sustained release small molecular drugs and penetrate soft tissue. Overall, the HBCMA-based microneedles show promising potential in non-dermal drug delivery applications.

Development of cultivable alginate fibers for an ideal cell-cultivated meat scaffold and production of hybrid cultured meat.

Slaughtering animals for meat pose several challenges, including environmental pollution and ethical concerns. Scaffold-based cell-cultivated meat has been proposed as a solution to these problems, however, the utilization of animal-derived materials for scaffolding or the high cost of production remains a significant challenge. Alginate is an ideal material for cell-cultivated meat scaffolds but has poor cell adhesion properties. To address this issue, we achieved 82 % cell adhesion coverage by controlling the specific structure generated during the ionic crosslinking process of alginate. Post 11 days of culture; we evaluated cell adhesion, differentiation, and aligned cell networks. The cell growth increased by 12.7 % compared to the initial seeding concentration. Finally, we created hybrid cell-cultivated meat by combining single-cell protein from mycelium and cell-cultivated meat. This is non-animal based, edible, cost-effective, and has a desirable texture by blending cell-cultivated meat with a meat analogue. In summary, the creation of improved alginate fibers can effectively tackle various obstacles encountered in the manufacturing of cell-cultivated meat. This includes enhancing cell adhesion, reducing costs, and streamlining the production procedure.

Historical Review and Future of Cardiac Xenotransplantation.

Along with the development of immunosuppressive drugs, major advances on xenotransplantation were achieved by understanding the immunobiology of xenograft rejection. Most importantly, three predominant carbohydrate antigens on porcine endothelial cells were key elements provoking hyperacute rejection: α1,3-galactose, SDa blood group antigen, and N-glycolylneuraminic acid. Preformed antibodies binding to the porcine major xenoantigen causes complement activation and endothelial cell activation, leading to xenograft injury and intravascular thrombosis. Recent advances in genetic engineering enabled knock-outs of these major xenoantigens, thus producing xenografts with less hyperacute rejection rates. Another milestone in the history of xenotransplantation was the development of co-stimulation blockaded strategy. Unlike allotransplantation, xenotransplantation requires blockade of CD40-CD40L pathway to prevent T-cell dependent B-cell activation and antibody production. In 2010s, advanced genetic engineering of xenograft by inducing the expression of multiple human transgenes became available. So-called 'multi-gene' xenografts expressing human transgenes such as thrombomodulin and endothelial protein C receptor were introduced, which resulted in the reduction of thrombotic events and improvement of xenograft survival. Still, there are many limitations to clinical translation of cardiac xenotransplantation. Along with technical challenges, zoonotic infection and physiological discordances are major obstacles. Social barriers including healthcare costs also need to be addressed. Although there are several remaining obstacles to overcome, xenotransplantation would surely become the novel option for millions of patients with end-stage heart failure who have limited options to traditional therapeutics.

Erratum: Correction of Authors in the Article "Relevance Index Regional Variation by Each Disease and Its Essential Medical Field: A Retrospective Data Analysis From 2016-2020 in Korea".

This corrects the article on p. e130 in vol. 38, PMID: 37096313.

Relevance Index Regional Variation by Each Disease and Its Essential Medical Field: A Retrospective Data Analysis From 2016-2020 in Korea.

BACKGROUND: To precisely build a healthcare delivery system at regional levels, local patients' healthcare service utilization patterns must be examined. Hence, this study utilized trend analysis of the relevance index of each disease of each essential medical service field at the municipal and provincial levels. METHODS: This study analyzed customized databases released by the National Health Insurance Service from 2016-2020. Diseases defined in the Korean National Burden of Disease (KNBD) study were categorized into the following essential medical service fields: trauma care, cardiocerebrovascular, maternal and neonatal, mental health, infection, cancer, older adults' care and rehabilitation, and others. Relevance index, the percentage of medical service utilization in a region by the residents of that region relative to their total medical service utilization, was examined by region (17 municipal and provincial regions) and disease area. The relevance index was determined based on the number of patients and the total out-of-pocket expenses. RESULT: Eight of the 17 regions showed over a 90.0% relevance index in the infection area. In the cancer area, 14 regions (not including Seoul, Daegu, and Busan) had a relevance index lower than 75.0%. Throughout the analysis period (2016-2020), there were no significant variations in the relevance index. Diseases such as bone and connective tissue cancer (39.0%), neural tube defects (16.7%), and autism (57.1%) had low relevance index in the essential medical service fields. In all 17 regions, the relevance index of inpatients was lower than that of outpatients, and that for out-of-pocket expenses was lower than that based on the number of patients. CONCLUSION: The relevance index of major diseases of each essential medical service field calculated in this study can provide good indicators for monitoring the level of an independent regional healthcare delivery system.

Challenge exposure to whole cigarette smoke condensate upregulates locomotor sensitization by stimulating α4ß2 nicotinic acetylcholine receptors in the nucleus accumbens of rats.

Nicotine, the primary addictive substance in tobacco, produces the psychomotor, rewarding, and reinforcing effects of tobacco dependence by stimulating nicotinic acetylcholine receptors (nAChRs) in the brain. The present study determined that α4ß2 nAChRs regulate locomotor sensitization by altering dopamine concentration in the nucleus accumbens (NAc) after systemic challenge exposure to whole cigarette smoke condensate (WCSC). Rats were administered subcutaneous injection of WCSC (0.2 mg/kg nicotine/day) for 7 consecutive days and then re-exposed to WCSC after 3 days of withdrawal. Challenge exposure to WCSC significantly increased locomotor activity. This increase was decreased by the subcutaneous injection of the α4ß2 nAChR antagonist, DHßE (3 mg/kg), but not by the intraperitoneal injection of the α7 nAChR antagonist, MLA (5 mg/kg). In parallel with a decrease in locomotor activity, blockade of α4ß2 nAChRs with DHßE decreased dopamine concentration in the NAc which was elevated by challenge exposure to WCSC. These findings suggest that challenge WCSC leads to the expression of locomotor sensitization by elevating dopamine concentration via stimulation of α4ß2 nAChRs expressed in neurons of the NAc in rats.

Efficient Myogenic/Adipogenic Transdifferentiation of Bovine Fibroblasts in a 3D Bioprinting System for Steak-Type Cultured Meat Production.

The interest in cultured meat is increasing because of the problems with conventional livestock industry. Recently, many studies related to cultured meat have been conducted, but producing large-sized cultured meat remains a challenge. It is aimed to introduce 3D bioprinting for producing large cell aggregates for cultured meat production. A hydrogel scaffold is produced at the centimeter scale using a bioink consisting of photocrosslinkable materials for digital light processing-based (DLP) printing, which has high printing accuracy and can produce geometrically complex structures. The light exposure time for hydrogel photopolymerization by DLP bioprinting is optimized based on photorheometry and cell viability assays. Naturally immortalized bovine embryonic fibroblast cells transformed with MyoD and PPARγ2 instead of primary cells are used as the latter have difficulties in maintaining stemness and are associated with animal ethics issues. The cells are mixed into the hydrogel for printing. Myogenesis and adipogenesis are induced simply by changing the medium after printing. Scaffolds are obtained successfully with living cells and large microchannels. The cooked cultured meat maintains its size and shape upon cutting. The overall dimensions are 3.43 cm × 5.53 cm × 0.96 cm. This study provides proof-of-concept for producing 3D cultured meat using bioinks.

Triple-conjugated photo-/temperature-/pH-sensitive chitosan with an intelligent response for bioengineering applications.

Hybrid-crosslinked systems, which can be formed using heat and visible light, are significant for improving the stability of hydrogels under physiological conditions. However, several challenges for their practical application remain, such as shrinking under culture medium conditions or the neutral pH in the small intestine. Therefore, a multi-sensitive hydrogel with response to external conditions has been designed and prepared, which could be employed as a biopolymer ink formulation for three-dimensional printing in bioengineering applications. When exposed to body temperature and visible light, the N-succinyl hydroxybutyl methacrylated chitosan (NS-HBC-MA) undergoes a sol-gel phase transition. The NS-HBC-MA hydrogel exhibits pH-responsive swelling, effectively preventing shrinkage at a neutral pH. Furthermore, NS-HBC-MA hydrogel demonstrates excellent biocompatibility and biodegradability. This study demonstrates that the NS-HBC-MA hydrogel has significant potential for various applications, including wound healing, delivery systems, and tissue engineering.

Surgical and Electrical Anatomy of the Inter-Nodal and Intra-Atrial Conduction System in the Heart.

An anatomical understanding of the atrial myocardium is crucial for surgeons and interventionists who treat atrial arrhythmias. We reviewed the anatomy of the inter-nodal and intra-atrial conduction systems. The anterior inter-nodal route (#1) arises from the sinus node and runs through the ventral wall of the atrial chambers. The major branch of route #1 approaches the atrioventricular node from the anterior aspect. Other branches of route #1 are Bachmann's bundle and a vestibular branch around the tricuspid valve. The middle inter-nodal route (#2) begins with a broad span of fibers at the sinus venarum and extends to the superior limbus of the oval fossa. The major branch of route #2 joins with the branch of route #1 at the anterior part of the atrioventricular node. The posterior inter-nodal route (#3) is at the terminal crest and gives rise to many branches at the pectinate muscles of the right atrium and then approaches the posterior atrioventricular node after joining with the vestibular branch of route #1. The branches of the left part of Bachmann's bundle and the branches of the second inter-nodal route form a thin myocardial network at the posterior wall of the left atrium. These anatomical structures could be categorized into major routes and side branches. There are 9 or more anatomical circles in the atrial chambers that could be structural sites for macro re-entry. The implications of normal and abnormal structures of the myocardium for the pathogenesis and treatment of atrial arrhythmias are discussed.

Improving Printability of Digital-Light-Processing 3D Bioprinting via Photoabsorber Pigment Adjustment.

Digital-light-processing (DLP) three-dimensional (3D) bioprinting, which has a rapid printing speed and high precision, requires optimized biomaterial ink to ensure photocrosslinking for successful printing. However, optimization studies on DLP bioprinting have yet to sufficiently explore the measurement of light exposure energy and biomaterial ink absorbance controls to improve the printability. In this study, we synchronized the light wavelength of the projection base printer with the absorption wavelength of the biomaterial ink. In this paper, we provide a stepwise explanation of the challenges associated with unsynchronized absorption wavelengths and provide appropriate examples. In addition to biomaterial ink wavelength synchronization, we introduce photorheological measurements, which can provide optimized light exposure conditions. The photorheological measurements provide precise numerical data on light exposure time and, therefore, are an effective alternative to the expendable and inaccurate conventional measurement methods for light exposure energy. Using both photorheological measurements and bioink wavelength synchronization, we identified essential printability optimization conditions for DLP bioprinting that can be applied to various fields of biological sciences.

Serial ultrastructural evaluation of myocardial ischemic injury after infusion of del Nido cardioplegia in the human heart.

OBJECTIVES: The safe ischemic time after a single-dose del Nido cardioplegia (DNC) infusion has not yet been established. This study evaluated the progression of myocardial ischemic injury to establish the safe ischemic time after a single-dose DNC infusion in the human heart using a transmission electron microscope. METHODS: Seven hearts extracted from heart transplant recipients after infusion of 1000 mL single-dose DNC were evaluated. Serial left ventricular myocardial tissue samples were collected every 30 minutes for 180 minutes. Ischemic injuries in the mitochondria and nuclei were scored from 0 to 3 (0 = normal, 0.5 = slight, 1 = moderate, 2 = severe, and 3 = irreversible). RESULTS: At the time of extraction, 83.5% of the mitochondria were normal. The proportion of mitochondria with moderate ischemic injury increased gradually from 1.4% at extraction to 52.5% at 180 minutes. From 90 minutes to 180 minutes, the proportion of mitochondria with severe and irreversible injury increased from 0.8% to 4.4% and 0.3% to 1.3%, respectively. A significant linear correlation was identified between the average ischemic injury score of mitochondria and ischemic time (P < .001). Most nuclei showed moderate to severe ischemic injury at every time point (61.0%-85.2%). A significant linear correlation was also found between the average ischemic injury score of nuclei and ischemic time (P < .001). CONCLUSIONS: Myocardial ischemic injury progresses gradually, and irreversible ischemic injury begins to occur 90 minutes after initial DNC infusion in the adult human heart. Therefore, redosing of DNC may be required after 90 minutes of aortic crossclamp time during adult cardiac surgery.

Photo-Cross-Linkable Human Albumin Colloidal Gels Facilitate In Vivo Vascular Integration for Regenerative Medicine.

Biodegradable cellular and acellular scaffolds have great potential to regenerate damaged tissues or organs by creating a proper extracellular matrix (ECM) capable of recruiting endogenous cells to support cellular ingrowth. However, since hydrogel-based scaffolds normally degrade through surface erosion, cell migration and ingrowth into scaffolds might be inhibited early in the implantation. This could result in insufficient de novo tissue formation in the injured area. To address these challenges, continuous and microsized strand-like networks could be incorporated into scaffolds to guide and recruit endogenous cells in rapid manner. Fabrication of such microarchitectures in scaffolds is often a laborious and time-consuming process and could compromise the structural integrity of the scaffold or impact cell viability. Here, we have developed a fast single-step approach to fabricate colloidal hydrogels, which are made up of randomly packed human serum albumin-based photo-cross-linkable microparticles with continuous internal networks of microscale voids. The human serum albumin conjugated with methacrylic groups were assembled to microsized aggregates for achieving unique porous structures inside the colloidal gels. The albumin hydrogels showed tunable mechanical properties such as elastic modulus, porosity, and biodegradability, providing a suitable ECM for various cells such as cardiomyoblasts and endothelial cells. In addition, the encapsulated cells within the hydrogel showed improved cell retention and increased survivability in vitro. Microporous structures of the colloidal gels can serve as a guide for the infiltration of host cells upon implantation, achieving rapid recruitment of hematopoietic cells and, ultimately, enhancing the tissue regeneration capacity of implanted scaffolds.

Environmental health survey for children residing near mining areas in South Gobi, Mongolia.

BACKGROUND: We evaluated the level and factors of heavy metal exposure to children residing in the Togttsetsii, Khanbogd, and Bayandalai soums of South Gobi province, Mongolia. METHODS: A total of 118 children aged 9-12 years were surveyed, and the level of heavy metal exposure in their bodies was investigated. Exposure was investigated by measuring concentrations of heavy metals such as cadmium, lead, and mercury in the blood; mercury concentration in the hair; and total arsenic in the urine. RESULTS: Blood cadmium concentration had geometric averages of 0.16 µg/L in the children from Bayandalai, 0.15 µg/L Tsogttsetsii, and 0.16 µg/L Khanbogd. Blood lead concentration showed a relatively higher geometric average of 7.42 µg/dL in the children from Bayandalai compared to 4.78 µg/dL and 5.15 µg/dL in those from Tsogttsetsii and Khanbogd, respectively. While blood mercury concentration was the highest in the children from Bayandalai, with a value of 0.38 µg/L, those from Tsogttsetsii and Khanbogd had similar concentrations of 0.29 µg/L and 0.29 µg/L, respectively. Hair mercury concentration was the highest in the children from Bayandalai, with a value of 78 µg/g, a particularly significant difference, with a concentration of 0.50 µg/g in those from Khanbogd. Urine arsenic concentration was the highest in the children from Khanbogd, with a value of 36.93 µg/L; it was 26.11 µg/L in those from Bayandalai and 23.89 µg/L in those from Tsogttsetsii. CONCLUSIONS: The high blood lead concentration of children in Bayandalai was judged to be due to other factors in addition to mine exposure; the reason why blood and hair mercury concentration was higher in children from Bayandalai may have been due to exposure to many small-scale gold mines in the area. In the case of Khanbogd, it was estimated that the high arsenic level in urine was caused by the effect of mines.

Myocarditis-induced Sudden Death after BNT162b2 mRNA COVID-19 Vaccination in Korea: Case Report Focusing on Histopathological Findings.

We present autopsy findings of a 22-year-old man who developed chest pain 5 days after the first dose of the BNT162b2 mRNA vaccine and died 7 hours later. Histological examination of the heart revealed isolated atrial myocarditis, with neutrophil and histiocyte predominance. Immunohistochemical C4d staining revealed scattered single-cell necrosis of myocytes which was not accompanied by inflammatory infiltrates. Extensive contraction band necrosis was observed in the atria and ventricles. There was no evidence of microthrombosis or infection in the heart and other organs. The primary cause of death was determined to be myocarditis, causally-associated with the BNT162b2 vaccine.

Cardiac toxicity from bisphenol A exposure in human-induced pluripotent stem cell-derived cardiomyocytes.

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is widely used in a variety of products, including plastics, medical equipment and receipts. Hence, most people are exposed to BPA through the skin, via inhalation and via the digestive system, and such exposure has been linked to cardiovascular diseases including coronary artery disease, hypertension, atherosclerosis, and myocardial infarction. However, the underlying mechanisms of cardiac dysfunction caused by BPA remain poorly understood. In this study, we found that BPA exposure altered cardiac function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Acute BPA exposure in hiPSC-CMs resulted in reduced field potential, as measured by multielectrode array (MEA). Furthermore, we observed that BPA dose-dependently inhibited ICa, INa or IKr channels. In addition, BPA exposure dose-dependently inhibited calcium transients and contraction in hiPSC-CMs. Our findings suggest that BPA exposure leads to cardiac dysfunction and cardiac risk factors such as arrhythmia.

Assessment of Lead and Mercury Exposure Levels in the General Population of Korea Using Integrated National Biomonitoring Data.

In Korea, the estimated values of blood lead (Pb) and mercury (Hg) levels differ between two national-level biomonitors, namely the Korean National Environmental Health Survey and the Korea National Health and Nutrition Examination Survey. The present study used integrated data from these surveys to estimate the representative values of the change in concentration and recent distribution characteristics. The yearly trend of age-standardized exposure levels in regular adults was identified, and the geometric mean (GM) adjusted according to demographic characteristics was presented. Age-standardized GM for blood Pb and Hg in the integrated data was 2.06 and 3.64 µg/L in 2008, respectively, which decreased to 1.55 and 2.92 µg/L, respectively, by 2017. Adjusted GMs from most recently conducted surveys (2015-2017) were 1.61 and 2.98 µg/L for blood Pb and Hg, respectively. In particular, the adjusted percentage of blood Hg exceeding the reference value of 5 µg/L was 20.79%. While the blood Pb and Hg exposure levels are decreasing in Korea, the levels remain high relative to those in other countries. The Hg levels exceeded the reference value in many individuals. Therefore, continued biomonitoring must be conducted, and a reduction plan and exposure management are needed for harmful metals, including Hg.

Necessity of Assessing Biological Exposure to Arsenic Species by Two Representative Analytical Methods.

Arsenic (As) exists as highly toxic chemical species. Chronic exposure to its inorganic form can cause multiple organ failure and skin cancer in humans, warranting the need to determine the toxicity of each chemical species. This study evaluated the proportions of exposure to four chemical species of As (cAs), namely arsenite (AsIII), arsenate (AsV), monomethylarsinic acid (MMA), and dimethylarsenic acid (DMA), and it confirmed the necessity of evaluating biological exposure to cAs. Urine samples were collected from 457 subjects residing near 103 abandoned metal mines. Hydride generation atomic absorption spectroscopy (HG-AAS) was performed to measure the combined concentration of four cAs (hAsAAS). High-performance liquid chromatography and inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) were performed to determine the concentrations of the individual cAs and the sum of the four cAs (hAsICP). The proportions of AsV and MMA were relatively higher in the low-hAsICP concentration section. These findings suggest that hAsAAS, which is mainly used for its cost-efficiency, is limited for evaluating exposure. Though hAsAAS was found to exist in a low concentration, highly toxic AsV and MMA could be observed in high concentrations. Therefore, HPLC-ICP-MS is recommended for assessing cAs in environmentally vulnerable areas such as abandoned metal mines.

Feasibility study on stereotactic radiotherapy for total pulmonary vein isolation in a canine model.

We tested the feasibility of pulmonary vein (PV) and left atrial (LA) posterior wall isolation using non-invasive stereotactic ablative body radiotherapy (SABR) and investigated pathological changes in irradiated lesions in a canine model. Seven male Mongrel dogs received single-fraction 33 Gy SABR. We designed the en-bloc circular target of total PVs and LA posterior wall to avoid the esophagus. The circular box lesion included the LA roof and ridge, low posterior wall, and posterior interatrial septum. At 6 weeks or 4 months post-SABR, electrical isolation of the SABR lesion was confirmed using LA posterior wall pacing, and histopathological review was performed. Electrical isolation of all PVs and the LA posterior wall was achieved in three of five dogs in the 4-month group. There was one target failure and one sudden death at 15 weeks. Although two dogs in the 6-week group failed to achieve electrical lesion isolation, the irradiated atrial myocardium showed diffuse hemorrhage with inflammatory cell infiltration. In successfully isolated 4-month model dogs, we observed transmural fibrotic scarring with extensive fibrosis on irradiated atrial tissue. The findings suggest that this novel circular box-design radiotherapy technique using SABR could be applied to humans after further studies are conducted to confirm safety.