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Introduction: Bevacizumab is among the most frequently used drugs in cancer treatment. There is evidence that some anti-angiogenic drugs reduce flap survival, but it is unclear whether this applies to Bevacizumab. We investigated the effect of Bevacizumab on the viability of free flaps in rats. Methods: The animals were randomly assigned to one of three groups. The Graft group received intravascular saline and was submitted to a full-thickness skin graft. The Flap-Saline and the Flap-BVZ groups underwent a free groin flap after receiving, respectively, intravascular saline solution or intravascular administration of Bevacizumab. Results: The Graft group showed a lower percentage of the viable area (22.81%) relative to the Flap-Saline (83.98%; p

For the advancement of porcine xenotransplantation for clinical use in type 1 diabetes mellitus, the concerns of a sustainable and safe digestion enzyme blend must be overcome. Incorporating good manufacturing practices (GMP) can facilitate this through utilizing GMP-grade enzymes. In conjunction, still taking into account the cost-effectiveness, a wide concern. We evaluated how GMP-grade enzyme blends impact our piglet islets and their long-term effects.  Preweaned porcine islets (PPIs) were isolated from 8- to 10-day-old pigs. Digestion enzyme blends, collagenase type V (Type V), collagenase AF-1 GMP-grade with collagenase NB 6 GMP-grade (AF-1 and NB 6), and collagenase AF-1 GMP-grade with collagenase neutral protease AF GMP-grade (AF-1 and NP AF) were compared. Islet quality control assessments, islet yield, viability, and function, were performed on days 3 and 7, and cell content was performed on day 7.  GMP-grade AF-1 and NB 6 (17,209 ± 2,730 islet equivalent per gram of pancreatic tissue [IE/g] on day 3, 9,001 ± 1,034 IE/g on day 7) and AF-1 and NP AF (17,214 ± 3,901 IE/g on day 3, 8,833 ± 2,398 IE/g on day 7) showed a significant increase in islet yield compared to Type V (4,618 ± 1,240 IE/g on day 3, 1,923 ± 704 IE/g on day 7). Islet size, viability, and function showed comparable results in all enzyme blends. There was no significant difference in islet cellular content between enzyme blends.  This study demonstrated a comparison of GMP-grade collagenase enzyme blends and a standard crude collagenase enzyme in preweaned-aged porcine, a novel topic in this age. GMP-grade enzyme blends of AF-1 and NB 6 and AF-1 and NP AF resulted in substantially higher yields and as effective PPIs compared to Type V. In the long run, considering costs, integrity, and sustainability, GMP-grade enzyme blends are more favorable for clinical application due to high reproducibility in comparison to undefined manufacturing processes of standard enzymes.

Different approaches have investigated the effects of different extracellular matrices (ECMs) and three-dimensional (3D) culture on islet function, showing encouraging results. Ideally, the proper scaffold should mimic the biochemical composition of the native tissue as it drives numerous signaling pathways involved in tissue homeostasis and functionality. Tissue-derived decellularized biomaterials can preserve the ECM composition of the native tissue making it an ideal scaffold for 3D tissue engineering applications. However, the decellularization process may affect the retention of specific components, and the choice of a proper detergent is fundamental in preserving the native ECM composition. In this study, we evaluated the effect of different decellularization protocols on the mechanical properties and biochemical composition of pancreatic ECM (pECM) hydrogels. Fresh porcine pancreas tissue was harvested, cut into small pieces, rinsed in water, and treated with two different detergents (sodium dodecyl sulfate [SDS] or Triton X-100) for 1 day followed by 3 days in water. Effective decellularization was confirmed by PicoGreen assay, Hoescht, and H&E staining, showing no differences among groups. Use of a protease inhibitor (PI) was also evaluated. Effective decellularization was confirmed by PicoGreen assay and hematoxylin and eosin (H&E) staining, showing no differences among groups. Triton-treated samples were able to form a firm hydrogel under appropriate conditions, while the use of SDS had detrimental effects on the gelation properties of the hydrogels. ECM biochemical composition was characterized both in the fresh porcine pancreas and all decellularized pECM hydrogels by quantitative mass spectrometry analysis. Fibrillar collagen was the major ECM component in all groups, with all generated hydrogels having a higher amount compared with fresh pancreas. This effect was more pronounced in the SDS-treated hydrogels when compared with the Triton groups, showing very little retention of other ECM molecules. Conversely, basement membrane and matricellular proteins were better retained when the tissue was pretreated with a PI and decellularized in Triton X-100, making the hydrogel more similar to the native tissue. In conclusion, we showed that all the protocols evaluated in the study showed effective tissue decellularization, but only when the tissue was pretreated with a PI and decellularized in Triton detergent, the biochemical composition of the hydrogel was closer to the native tissue ECM. Impact Statement The article compares different methodologies for the generation of a pancreas-derived hydrogel for tissue engineering applications. The biochemical characterization of the newly generated hydrogel shows that the material retains all the extracellular molecules of the native tissue and is capable of sustaining functionality of the encapsulated beta-cells.

Background and Objective: The discrepancy between donor organ availability and demand leads to a significant waiting-list dropout rate and mortality. Although quantitative tools such as the Donor Risk Index (DRI) help assess organ suitability, many potentially viable organs are still discarded due to the lack of universally accepted markers to predict post-transplant outcomes. Normothermic machine perfusion (NMP) offers a platform to assess viability before transplantation. Thus, livers considered unsuitable for transplantation based on the DRI can be evaluated and potentially transplanted. During NMP, various viability criteria have been proposed. These criteria are neither homogeneous nor consensual. In this review, we aimed to describe the viability criteria during NMP and evaluate their ability to predict hepatic graft function following transplantation. We conducted a PubMed search using the terms 'liver transplantation', 'normothermic machine perfusion' and 'assessment', including only English publications up to February 2024. Viability assessment during NMP includes multiple hepatocellular and cholangiocellular criteria. Lactate clearance and bile production are commonly used indicators, but their ability to predict post-transplant outcomes varies significantly. The predictive value of cholangiocellular criteria such as bile pH, bicarbonate and glucose levels remains under investigation. Novel markers, such as microRNAs and proteomic profiles, offer the potential to enhance graft evaluation accuracy and provide insights into the molecular mechanisms underlying liver viability. Combining perfusion parameters with biomarkers may improve the prediction of long-term graft survival. Future research should focus on standardising viability assessment protocols and exploring real-time biomarker evaluations, which could enhance transplantation outcomes and expand the donor pool., (© 2025 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Formal assessment of myocardial viability (MV) is challenging in acute myocardial infarction-related cardiogenic shock (AMI-CS) patients receiving Impella mechanical circulatory support, as the cardiac magnetic resonance gold standard technique is not feasible due to the metallic components of the device. 18-fluorodesoxyglucose metabolic myocardial positron emission tomography ( 18 FDG-PET) may represent a valid and feasible alternative to obtain semi-quantitative and objective evidence of MV during Impella support. We hereby report the first series of sequential AMI-CS patients who received 18 FDG-PET scanning to assess MV during Impella support to demonstrate the safety and feasibility of this approach. In this cohort no adverse events occurred during 18 FDG-PET scans, and all images were of excellent quality. This study provides a pragmatic guidance on how to perform this imaging modality during Impella support and finally confirms the safety and feasibility of this advanced imaging method also in this vulnerable cohort of patients., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Living myocardial slices (LMS) are ultrathin sections of adult myocardium that can be maintained in culture. These slices provide a unique platform for studying interactions between cardiomyocytes (CMs), other cardiac cell types, and the extracellular matrix while maintaining the cytoarchitecture and electrical phenotype of CMs over extended periods. Despite their advantages over other cardiac models, LMS have limitations, particularly their reliance on slice quality. The primary factor influencing the quality of the slices is the method used to process the cardiac tissue block. Current methods typically require immediate slice preparation following the excision of the tissue block, which restricts the timing of experiments. To address this limitation, we developed a simple procedure for cryopreserving human adult myocardium, allowing the preparation of LMS at a later stage. The protocol provides a list of required equipment and reagents, as well as a detailed description of the methodology for processing the myocardium and slice preparation. We present typical results demonstrating that cryopreserved human cardiac tissue retains biomass and structural integrity comparable to freshly obtained myocardium. Furthermore, we assessed the LMS derived from both fresh and cryopreserved samples. Histological analysis confirmed the preservation of viability, normal cytomorphology, and gap junctions between CMs in all LMS after 24 h and up to 5 days of culture in the absence of electrical stimulation. Cryopreservation extends the interval between tissue collection and LMS preparation, facilitating longer-term and more complex experiments. Further research into the impact of cryopreservation on various cardiac cell types will promote better donor organ management and efficient banking of cardiac samples from a multitude of donors and disease states. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Preparation and preservation of human adult myocardium Basic Protocol 2: Preparation of adult living myocardial slices from cryopreserved blocks., (© 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC.)

The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant.

BackgroundA novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI-DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model.Methods and resultsDual contrast MEMRI-DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 ± 7 %*** vs. 19 ± 5 %, 29 ± 3 %*** vs. 22 ± 4 %, and 31 ± 2 %*** vs 18 ± 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs).ConclusionThe improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI-DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.

Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2. We generated mice that were either deficient or hypomorphic for SREBP-2. SREBP-2 deficiency generally caused death during embryonic development. Analyses of Srebf2(-/-) embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2(-/-) mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specific manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue.

Study Question: Is it possible to establish an ex vivo endometriosis model using cryopreserved endometriotic tissue fragments?, Summary Answer: Cryopreserved endometriotic tissue fragments remain viable after thawing and during at least 3 days of culture and can therefore be used to establish an ex vivo endometriosis model to efficiently test potential therapeutic agents., What Is Known Already: Endometriosis is the most prevalent benign gynecologic disease with an enormous societal burden; however, curative therapies are still lacking. To efficiently test potential new therapies, an ex vivo model based on previously cryopreserved endometriotic tissue that recapitulates the different endometriosis subtypes and their microenvironment is highly desirable., Study Design, Size, Duration: Endometriotic tissue fragments of three different subtypes were obtained from 28 patients by surgical resection. After cryopreservation and thawing, viability and metabolic activity of these tissue fragments were assessed. Viability was compared with fresh fragments from 11 patients directly after surgical removal. Experimental intervention studies were performed in cryopreserved and thawed tissue fragments from two patients to confirm the usability of these tissues for ex vivo intervention studies., Participants/materials, Setting, Methods: Endometriotic tissue fragments (n = 45) were cryopreserved according to three different protocols. After thawing, fragments were cultured for 24 h. A resazurin-based assay was performed to assess the metabolic activity of the tissue fragments. In addition, cell type-specific viability was analyzed by VivaFix, Hoechst 33342, and α-smooth muscle actin immunofluorescence staining and confocal microscopy. The presence of endometriosis was histologically confirmed based on hematoxylin-eosin staining. Cryopreserved and thawed tissue fragments were treated for 72 h with pirfenidone or metformin and COL1A1 and CEMIP gene expressions were assessed using RT-PCR and RT-qPCR, either in the whole tissue fragments or in myofibroblasts isolated by laser capture microdissection., Main Results and the Role of Chance: Metabolic activity of endometriotic tissue fragments obtained from peritoneal (PER), ovarian (OMA), and deep (DE) endometriotic lesions was well preserved after cryopreservation in a dimethyl sulfoxide-based medium and was comparable with fresh tissue fragments. Relative metabolic activity compared to fresh tissue was 70% (CI: 92-47%) in PER, 43% (CI: 53-15%) in OMA and 94% (CI: 186-3%) in DE lesions. In fragments from PE lesions 92% (CI: 87-96%), from OMA lesions 95% (CI: 91-98%), and from DE lesions 88% (CI: 78-98%) of cells were viable after cryopreservation and thawing followed by a 24-h culture period. Differences in gene expression of fibrotic markers COL1A1 and CEMIP after 72-h treatment with pirfenidone or metformin could be detected in whole tissue fragments and in isolated myofibroblasts, indicating that cryopreserved and thawed endometriotic tissue fragments are suitable for testing anti-fibrotic interventions., Large Scale Data: N/A., Limitations, Reasons for Caution: Viability and metabolic activity of the endometriotic tissue fragments may have been partially compromised by damage sustained during the surgical procedure, contributing to inter-sample variance., Wider Implications of the Findings: The storage of viable endometriotic tissue fragments for later usage in an ex vivo model creates the possibility to efficiently test potential new therapeutic strategies and facilitates the exchange of viable endometriotic tissue between different research laboratories., Study Funding/competing Interest(s): This study was not financially supported by external funding. The authors declare no competing interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background:  This study was conducted to evaluate whether myocardial viability assessed with cardiac magnetic resonance (CMR) affected long-term clinical outcomes after coronary artery bypass grafting (CABG) in patients with ischemic cardiomyopathy (ICMP)., Methods:  Preoperative CMR with late gadolinium enhancement (LGE) was performed in 103 patients (64.9 ± 10.1 years, male:female = 82:21) with 3-vessel disease and left ventricular dysfunction (ejection fraction ≤ 0.35). Transmural extent of LGE was evaluated on a 16-segment model, and transmurality was graded on a 5-point scale: grades-0, absence; 1, 1 to 25%; 2, 26 to 50%; 3, 51 to 75%; 4, 76 to 100%. Median follow-up duration was 65.5 months (interquartile range = 27.5-95.3 months). Primary endpoint was the composite of all-cause mortality or hospitalization for congestive heart failure., Results:  Operative mortality was 1.9%. During the follow-up, all-cause mortality and readmission for congestive heart failure occurred in 29 and 8 patients, respectively. The cumulative incidence of the primary endpoint was 31.3 and 46.8% at 5 and 10 years, respectively. Multivariable analysis demonstrated that the number of segments with LGE grade 4 was a significant risk factor (hazard ratio 1.42, 95% confidence interval 1.10-1.83, p  = 0.007) for the primary endpoint among the variables assessed by CMR. Other risk factors included age, dialysis, chronic obstructive pulmonary disease, and EuroSCORE II., Conclusion:  The number of myocardial segments with transmurality of LGE >75% might be a prognostic factor associated with the composite of all-cause mortality or hospitalization for congestive heart failure after CABG in patients with 3-vessel disease and ICMP., Competing Interests: None declared., (Thieme. All rights reserved.)

Report the effects of photobiomodulation (PBM) and therapeutic ultrasound (TUS) on the viability of TRAM in mice. Materials and Methods: Fifty-five mice Swiss were subjected to treatment for 5 days. Group 1, treatment was performed with the agents switched off. Groups 2 to 5 were treated with different wavelengths 660 and 830 nanometers (nm) and groups 6 to 11 with TUS of 1 and 3 MHz frequency. Macrometric analyses were performed using a specific camera and analyzed by the ImageJ® software. Thermographic analyses were performed with the Flir C2 and analyzed using the FLIR Tools software. Results: Group 9 obtained 95% of viable area on the 3rd day and 85% on the 5th day, showing the effectiveness of the TUS in the flap viability. Regarding skin temperature, there was a difference only in the immediate postoperative period in group 1, which had a lower temperature than the other groups. Conclusions: TUS demonstrated greater efficiency in maintaining the viability of TRAM. PBM 830 nm also demonstrated good results in the viability of TRAM. [ABSTRACT FROM AUTHOR]

PurposeEvaluate whether a decrease in apparent diffusion coefficient (ADC), associated with loss of tissue viability (LOTV), can be observed during the course of thermal ablation of the prostate.MethodsThermal ablation was performed in a healthy in vivo canine prostate model (N = 2, ages: 5 yr healthy, mixed breed, weights: 13-14 kg) using a transurethral high-intensity ultrasound catheter and was monitored using a strategy that interleaves diffusion weighted images and gradient-echo images. The two sequences were used to measure ADC and changes in temperature during the treatment. Changes in temperature were used to compute expected changes in ADC. The difference between expected and measured ADC, ADCDIFF, was analyzed in regions ranging from moderate hyperthermia to heat fixation. A receiver operator characteristic (ROC) curve analysis was used to select a threshold of detection of LOTV. Time of threshold activation, tLOTV, was compared with time to reach CEM43 = 240, tDOSE.ResultsThe observed relationship between temperature and ADC in vivo (2.2%/ °C, 1.94%-2.47%/ °C 95% confidence interval) was not significantly different than the previously reported value of 2.4%/ °C in phantom. ADCDIFF changes after correction for temperature showed a mean decrease of 25% in ADC 60 min post-treatment in regions where sufficient thermal dose (CEM43 > 240) was achieved. Following our ROC analysis, a threshold of 2.25% decrease in ADCDIFF for three consecutive time points was chosen as an indicator of LOTV. The ADCDIFF was found to decrease quickly (1-2 min) after reaching CEM43 = 240 in regions associated with heat fixation and more slowly (10-20 min) in regions that received slower heating.ConclusionsSimultaneous monitoring of ADC and temperature during treatment might allow for a more complete tissue viability assessment of ablative thermal treatments in the prostate. ADCDIFF decreases during the course of treatment may be interpreted as loss of tissue viability.

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

Abstract Background The translation from animal research into the clinical environment remains problematic, as animal systems do not adequately replicate the human in vivo environment. Bioreactors have emerged as a good alternative that can reproduce part of the human in vivo processes at an in vitro level. However, in vitro bone formation platforms primarily utilize stem cells only, with tissue based in vitro systems remaining poorly investigated. As such, the present pilot study explored the tissue behavior and cell survival capability within a new in vitro skeletal muscle tissue-based biomaterial organoid bioreactor system to maximize future bone tissue engineering prospects. Results Three dimensional printed β-tricalcium phosphate/hydroxyapatite devices were either wrapped in a sheet of rat muscle tissue or first implanted in a heterotopic muscle pouch that was then excised and cultured in vitro for up to 30 days. Devices wrapped in muscle tissue showed cell death by day 15. Contrarily, devices in muscle pouches showed angiogenic and limited osteogenic gene expression tendencies with consistent TGF-ß 1 , COL4A1, VEGF-A, RUNX-2, and BMP-2 up-regulation, respectively. Histologically, muscle tissue degradation and fibrin release was seen being absorbed by devices acting possibly as a support for new tissue formation in the bioceramic scaffold that supports progenitor stem cell osteogenic differentiation. Conclusions These results therefore demonstrate that the skeletal muscle pouch-based biomaterial culturing system can support tissue survival over a prolonged culture period and represents a novel organoid tissue model that with further adjustments could generate bone tissue for direct clinical transplantations.

Previous studies have demonstrated the feasibility of laser irradiation (λ = 1.45 μm) in tandem with cryogen spray cooling (CSC) to reshape rabbit auricular cartilage using a total energy density of 14 J/cm(2). The aim of this study was to further explore and identify the dosimetry parameter space for laser output energy, CSC duration, and treatment cycles required to achieve shape change while limiting skin and cartilage injury. Ten New Zealand white rabbits were treated with the 1.45 μm diode laser combined with cryogen spray cooling (Candela Smoothbeam™, Candela Co., Wayland, MA, USA). The ear's central portion was bent around a cylindrical jig and irradiated in consecutive spots of 6 mm diameter (13 or 14 J/cm(2) per spot) along three rows encompassing the bend. CSC was delivered during irradiation in cycles consisting of 25-35 ms. At thin and thick portions of the ear, 4-7 and 6-10 treatment cycles were delivered, respectively. After surgery, ears were examined and splinted for 6 weeks. Treatment parameters resulting in acceptable (grades 1 and 2) and unacceptable (grade 3) skin injuries for thick and thin regions were identified, and shape change was observed. Confocal and histological analysis of cartilage tissue revealed several outcomes correlating to laser dosimetry, CSC duration, and treatment cycles. These outcomes included expansion of cartilage layers (thickening), partial cartilage injuries, and full-thickness cartilage injuries. We determined therapy thresholds for laser output energy, cryogen spray cooling duration, and treatment cycles in the rabbit auricular model. These parameters are a starting point for future clinical procedures aimed at correcting external ear deformities.

1. Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized. 2. The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups. 3. In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected. 4. Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs.

Purpose of Review: In an attempt to reduce waiting list mortality in liver transplantation, less-than-ideal quality donor livers from extended criteria donors are increasingly accepted. Predicting the outcome of these organs remains a challenge. Machine perfusion provides the unique possibility to assess donor liver viability pretransplantation and predict postreperfusion organ function., Recent Findings: Assessing liver viability during hypothermic machine perfusion remains challenging, as the liver is not metabolically active. Nevertheless, the levels of flavin mononucleotide, transaminases, lactate dehydrogenase, glucose and pH in the perfusate have proven to be predictors of liver viability. During normothermic machine perfusion, the liver is metabolically active and in addition to the perfusate levels of pH, transaminases, glucose and lactate, the production of bile is a crucial criterion for hepatocyte viability. Cholangiocyte viability can be determined by analyzing bile composition. The differences between perfusate and bile levels of pH, bicarbonate and glucose are good predictors of freedom from ischemic cholangiopathy., Summary: Although consensus is lacking regarding precise cut-off values during machine perfusion, there is general consensus on the importance of evaluating both hepatocyte and cholangiocyte compartments. The challenge is to reach consensus for increased organ utilization, while at the same time pushing the boundaries by expanding the possibilities for viability testing., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: We aim to provide a comprehensive review of the current state of knowledge of myocardial viability assessment in patients undergoing coronary artery bypass grafting (CABG), with a focus on the clinical markers of viability for each imaging modality. We also compare mortality between patients with viable myocardium and those without viability who undergo CABG., Methods: A systematic database search with meta-analysis was conducted of comparative original articles (both observations and randomized controlled studies) of patients undergoing CABG with either viable or nonviable myocardium, in EMBASE, MEDLINE, Cochrane database, and Google Scholar, from inception to 2022. Imaging modalities included were dobutamine stress echocardiography (DSE), cardiac magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET)., Results: A total of 17 studies incorporating a total of 2317 patients were included. Across all imaging modalities, the relative risk of death post-CABG was reduced in patients with versus without viability (random-effects model: odds ratio: 0.42; 95% confidence interval: 0.29-0.61; p < 0.001). Imaging for myocardial viability has significant clinical implications as it can affect the accuracy of the diagnosis, guide treatment decisions, and predict patient outcomes. Generally, based on local availability and expertise, either SPECT or DSE should be considered as the first step in evaluating viability, while PET or CMR would provide further evaluation of transmurality, perfusion metabolism, and extent of scar tissue., Conclusion: The assessment of myocardial viability is an essential component of preoperative evaluation in patients with ischemic heart disease undergoing surgical revascularization. Careful patient selection and individualized assessment of viability remain paramount., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals LLC.)

Coronary artery disease (CAD) is a prevalent cause of left ventricular dysfunction. Nevertheless, effective elective revascularization, particularly surgical revascularization, can enhance long-term outcomes and, in selected cases, global left ventricular contractility. The assessment of myocardial viability and scars is still relevant in guiding treatment decisions and selecting patients who are likely to benefit most from blood flow restoration. Although the most recent randomized studies challenge the notion of "hibernating myocardium" and the clinical usefulness of assessing myocardial viability, the advancement of imaging techniques still renders this assessment valuable in specific situations. According to the guidelines of the European Society of Cardiology, non-invasive stress imaging may be employed to define myocardial ischemia and viability in patients with CAD and heart failure before revascularization. Currently, several non-invasive imaging techniques are available to evaluate the presence and extent of viable myocardium. The selection of the most suitable technique should be based on the patient, clinical context, and resource availability. This narrative review evaluates the characteristics of available imaging modalities for assessing myocardial viability to determine the most appropriate therapeutic strategy., (© 2024 Wiley Periodicals LLC.)

Ischemic left ventricular dysfunction results from the combination of scar and areas of dysfunctional but viable myocardium that may improve contractile function with revascularization. The traditional paradigm states that an improvement in function after revascularization leads to improved health outcomes and that assessment of myocardial viability has a key role in predicting the benefit of revascularization and, therefore, is a prerequisite for the selection of patients to undergo this treatment option. A range of retrospective observational studies supported this "viability hypothesis". However, randomized prospective trials have not confirmed the interaction between myocardial viability and the treatment effect of revascularization, challenging the recovery of left ventricular function as the principal mechanism by which surgical revascularization improves prognosis. A conceptual shift from the traditional paradigm centered on the assessment of viability as a dichotomous variable to a more comprehensive approach founded on an alternative concept that the main goal of revascularization is to prevent further damage by protecting the residual viable myocardium from subsequent acute coronary events and ventricular arrhythmias is required.

Objective: Electrical contact burns of the scalp cause serious morbidity and mortality. Early necrotic bone debridement and flap cover are crucial for successful wound closure. 18 F Sodium Fluoride (NaF), with high bone-to-soft tissue activity ratio, is useful for bone viability assessment. This study evaluated the role of 18 F NaF PET-computed tomography (CT) in objectively defining the extent and depth of nonviable calvarial bone, to guide adequate bone debridement., Method: Of 20 patients referred to our institute with electrical contact burns of the scalp during a 2-year period, 15 were enrolled in the study. Two weeks after the initial management, tracer uptake pattern was noted on 18 F NaF PET-CT of the head and exposed bone measured. Surgical bone debridement was based on scan findings, followed by wound closure. All patients underwent clinical evaluation and follow-up scan 3 months after surgery., Results: Eight patients showed a central photopenic area in the exposed bone (maximum standardized uptake value [SUVmax] of 0.76 ± 0.14 with mean maximum dimensions 4.10 ± 1.76/2.67 ± 1.54 cm). High tracer uptake (SUVmax, 9.66 ± 6.03) was seen peripheral to the exposed bone (mean maximum dimensions, 8.14 ± 3.03/4.75 ± 1.61 cm). Postoperatively, there was no significant change in tracer uptake in the central debrided region or peri-debridement bone area under the flap. Clinically all patients showed a well-healed flap., Conclusion: 18 F NaF PET-CT appears useful for objective evaluation of skull bone viability and planning necrotic bone debridement in patients with electrical contact burns. However, additional studies with longer patient follow-up are required to validate these results., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The number of patients on the liver transplant waitlist continues to grow and far exceeds the number of livers available for transplantation. Normothermic machine perfusion (NMP) allows for ex-vivo perfusion under physiologic conditions with the potential to significantly increase organ yield and expand the donor pool., Recent Findings: Several studies have found increased utilization of donation after cardiac death and extended criteria brain-dead donor livers with implementation of NMP, largely due to the ability to perform viability testing during machine perfusion. Recently, proposed viability criteria include lactate clearance, maintenance of perfusate pH more than 7.2, ALT less than 6000 u/l, evidence of glucose metabolism and bile production. Optimization of liver grafts during NMP is an active area of research and includes interventions for defatting steatotic livers, preventing ischemic cholangiopathy and rejection, and minimizing ischemia reperfusion injury., Summary: NMP has resulted in increased organ utilization from marginal donors with acceptable outcomes. The added flexibility of prolonged organ storage times has the potential to improve time constraints and transplant logistics. Further research to determine ideal viability criteria and investigate ways to optimize marginal and otherwise nontransplantable liver grafts during NMP is warranted., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Procedures for cryopreserving embryos vary considerably, each having its specific advantages and disadvantages in terms of technical feasibility, embryo survival yield, temperature permissibility and species- or strain-dependent applicability. Here we report a high osmolality vitrification (HOV) method that is advantageous in these respects. Cryopreservation by vitrification is generally very simple, but, unlike slow freezing, embryos should be kept at a supercooling temperature (below -130°C) to avoid cryodamage. We overcame this problem by using an HOV solution containing 42.5% (v/v) ethylene glycol, 17.3% (w/v) Ficoll and 1.0 M sucrose. This solution is more viscous than other cryopreservation solutions, but easy handling of embryos was assured by employing a less viscous equilibration solution before vitrification. Most (>80%) embryos cryopreserved in this solution survived at -80°C for at least 30 days. Normal mice were recovered even after intercontinental transportation in a conventional dry-ice package for 2-3 days, indicating that special containers such as dry shippers with liquid nitrogen vapor are unnecessary. The HOV solution could also be employed for long-term storage in liquid nitrogen, as with other conventional cryoprotectants. Finally, we confirmed that this new vitrification method could be applied successfully to embryos of all six strains of mice we have tested so far. Thus, our HOV method provides an efficient and reliable strategy for the routine cryopreservation of mouse embryos in animal facilities and biomedical laboratories, and for easy and cheap transportation.

Purpose: Study aims to investigate the consistency of delayed enhancement cardiac magnetic resonance imaging (DE-CMR) and 18 F-FDG PET myocardial imaging in evaluating myocardial viability before CABG., Methods: The study analyzed data from 100 patients who were examined with DE-CMR, PET imaging, and echocardiography before and after CABG. All subjects were followed up for 6-12 month post- CABG., Results: DE-CMR and PET imaging have high consistency (90.1%; Kappa value = 0.71, p < 0.01) in determining myocardial viability. The degree of delayed enhancement was negatively correlated with the improvement in myocardial contractile function in this segment after revascularization (P < 0.001). The ratio of scarred myocardial segments and total DE score was significantly lower in the improvement group than non-improvement group. Multivariate regression identified that hibernating myocardium (OR = 1.229, 95%CI: 1.053-1.433, p = 0.009) was influencing factor of LVEF improvement after CABG., Conclusion: Both imaging techniques are consistent in evaluating myocardial viability. Detecting the number of hibernating myocardium by PET is also important to predict the left heart function improvement after CABG., (© 2024. The Author(s).)

This article will focus on the integration of tissue viability and lymphoedema services to improve outcomes for patients with leg ulceration. It will highlight why there is a need for lymphoedema specialist knowledge within the care of patients with leg ulceration and how the services are closely aligned. Lymphoedema can adversely affect wound healing and the article will provide case studies that highlight how developing a hybrid tissue viability and lymphoedema clinician or integration of the specialists can provide effective patient-centred care at reduced cost. The article offers potential strategies and suggestions on how to address inequalities in care and how to improve service provision.

Background: The translation from animal research into the clinical environment remains problematic, as animal systems do not adequately replicate the human in vivo environment. Bioreactors have emerged as a good alternative that can reproduce part of the human in vivo processes at an in vitro level. However, in vitro bone formation platforms primarily utilize stem cells only, with tissue based in vitro systems remaining poorly investigated. As such, the present pilot study explored the tissue behavior and cell survival capability within a new in vitro skeletal muscle tissue-based biomaterial organoid bioreactor system to maximize future bone tissue engineering prospects. Results: Three dimensional printed β-tricalcium phosphate/hydroxyapatite devices were either wrapped in a sheet of rat muscle tissue or first implanted in a heterotopic muscle pouch that was then excised and cultured in vitro for up to 30 days. Devices wrapped in muscle tissue showed cell death by day 15. Contrarily, devices in muscle pouches showed angiogenic and limited osteogenic gene expression tendencies with consistent TGF-ß1, COL4A1, VEGF-A, RUNX-2, and BMP-2 up-regulation, respectively. Histologically, muscle tissue degradation and fibrin release was seen being absorbed by devices acting possibly as a support for new tissue formation in the bioceramic scaffold that supports progenitor stem cell osteogenic differentiation. Conclusions: These results therefore demonstrate that the skeletal muscle pouch-based biomaterial culturing system can support tissue survival over a prolonged culture period and represents a novel organoid tissue model that with further adjustments could generate bone tissue for direct clinical transplantations. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to report the surgical outcomes of postoperative management of ice-cooling combined with moist-open dressing and intravenous prostaglandin E1 (PGE1) injection. Ice cooling as postoperative management was also discussed. Methods: Forty-one fingertip amputation of 38 patients between January 2007 and December 2017 were investigated retrospectively. Fingertip amputations were managed with postoperative ice bag application for 72 hours followed by moist open dressing and PGE1 injection. Results: Twenty-five composite grafts (61.0%) survived with complete healing at 8 weeks after surgery, with favorable outcomes in cases with low injury level (type I, 82.3%) and guillotine injury (77.8%). A higher survival rate was significantly correlated with female sex, guillotine injury, injury without osseous tissue (type I), and cold outdoor temperature (p<0.05). Multivariate analysis revealed that differences between types I and III injuries, injury mode, and outdoor temperature were independent clinical parameters associated with composite graft survival. Conclusion: The present study reported comparable results with postoperative ice cooling in cases with low injury level, guillotine injury, and low outdoor temperature. Prospective studies on the specific parameters of ice cooling and standards of manageable postoperative care should be conducted to enhance survival. [ABSTRACT FROM AUTHOR]

Background: In recent years the use of diced cartilage grafts in reconstructive surgery particulary rhinoplasty have been considered by most plastic surgeons. However, long-term resorption usually occurs. Stem cells are a powerful tool for reconstructive surgery to rebuild and maintain tissue with reduced complications. Since the adipose tissue-derived stem cells (ADSCs) can rebuild a wide variety of tissues such as skin, fat, bone and cartilage are used, this is a very good chance for cosmetic surgery. The aim of this study was to examine the effects of adipose-derived stem cells on the viability of diced cartilage grafts. Methods: This interventional study was performed on May 2014 in animal laboratory of Hazrat Fatima Hospital on 10 New Zealand white male rabbits, weighing 2000-2500 grams, approximately 12 to 16 weeks of age. Stem cells was harvested from inguinal adipose tissue of each rabbits. After completely removing the skin and perichondrium, cartilage became divided into two equal pieces using a scalpel. Then place the ear amputation was restored by nylon 4 zero. After weighing cartilages, on either side of the center line on the back of each rabbits, left and right, subcutaneous pocket created equal weight and each piece of cartilage was placed in an envelope. Stem cells were injected in one side and the other side was control. The cartilage weights were recorded both before implantation and after explantation. Evaluation of living chondrocytes was conducted 12 weeks after implantation. Results: The mean difference of cartilage weights was varied between two groups (intervention and control sides), So that the average was significantly higher in stem cell side than that in the control side (P= 0.021). The average number of live chondrocytes was significantly higher in the intervention side than the control side (P< 0.001). Conclusion: Despite the unclear mechanism, these results suggest that adipose-derived stem cells can maintain the viability of diced cartilage. Because adipose-derived stem cells are autologous and easy to harvest, they can be use to improve the long-term outcomes of diced cartilage grafting.

Pressure injury (PI) not only reduces the quality of life of patients but also is expensive to manage, placing a heavy financial burden on patients and their families, and society. Despite the increasing diversity of methods used to identify early PI, there are still few methods that can truly and accurately predict early PI. The sub-epidermal moisture scanner is the first U.S. Food and Drug Administration-authorized PI management device that can predict the occurrence and development of PI by measuring the level of local tissue bio-capacitance and monitoring the tissue viability. As an emerging diagnostic instrument, the sub-epidermal moisture scanner has already shown great advantages in clinical practice, which can promote the informatization, digitization, and intelligent prevention and management of PI. This paper introduces the pathophysiological mechanism of PI, elucidates the working principle and parameter settings of the sub-epidermal moisture scanner, its clinical application in monitoring tissue viability in early PI, and its limitation, and looks forward to its future development.

Background: Evaluation of standard echocardiographic examination with artificial intelligence may help in the diagnosis of myocardial viability and function recovery after acute coronary syndrome., Methods: Sixty-one consecutive patients with acute coronary syndrome were enrolled in the present study (43 men, mean age 61 ± 9 years). All patients underwent percutaneous coronary intervention (PCI). 533 segments of the heart echo images were used. After 12 ± 1 months of follow-up, patients had an echocardiographic evaluation. After PCI each patient underwent cardiac magnetic resonance (CMR) with late enhancement and low-dose dobutamine echocardiographic examination. For texture analysis, custom software was used (MaZda 5.20, Institute of Electronics).Linear and non-linear (neural network) discriminative analyses were performed to identify the optimal analytic method correlating with CMR regarding the necrosis extent and viability prediction after follow-up. Texture parameters were analyzed using machine learning techniques: Artificial Neural Networks, Namely Multilayer Perceptron, Nonlinear Discriminant Analysis, Support Vector Machine, and Adaboost algorithm., Results: The mean concordance between the CMR definition of viability and three classification models in Artificial Neural Networks varied from 42% to 76%. Echo-based detection of non-viable tissue was more sensitive in the segments with the highest relative transmural scar thickness: 51-75% and 76-99%. The best results have been obtained for images with contrast for red and grey components (74% of proper classification). In dobutamine echocardiography, the results of appropriate prediction were 67% for monochromatic images., Conclusions: Detection and semi-quantification of scar transmurality are feasible in echocardiographic images analyzed with artificial intelligence. Selected analytic methods yielded similar accuracy, and contrast enhancement contributed to the prediction accuracy of myocardial viability after myocardial infarction in 12 months of follow-up.

Background Tissue necrosis caused by insufficient perfusion is a major complication in flap transfer. This study evaluated whether treatment with cilostazol or hydroalcoholic extract of seeds of Euterpe oleracea Mart. (açaí) protects the transverse rectus abdominis myocutaneous (TRAM) flap against ischemic damage in hamsters. Materials and methods Fifty-four hamsters were divided into three oral treatment groups: placebo, açaí, or cilostazol. Caudally based, unipedicled TRAM flaps were raised, sutured back, classified into four vascular zones (I-IV), and evaluated for tissue viability, capillary blood flow (CBF), perfused vessel density (PVD), and microvascular flow index (MFI) by orthogonal polarization spectral imaging at three time points: immediately postoperatively (IPO), 24 h postoperatively (24hPO), and 7 d postoperatively (7POD). Results Comparing to placebo, açaí increased PVD at IPO and açaí and cilostazol increased CBF and PVD at 24hPO in zone I; cilostazol increased CBF, PVD, and MFI at IPO, and CBF at 24hPO in zone II; açaí and cilostazol increased CBF at all time points and PVD and MFI at IPO and 24hPO in zone III; cilostazol increased CBF at IPO and 7POD, açaí increased CBF at 7POD, and both increased PVD and MFI at all time points in zone IV; and açaí and cilostazol increased the percentage of viable area in zones III and IV. Conclusions Açaí and cilostazol treatments had a protective effect against ischemic damage to TRAM flaps in hamsters, improving microvascular blood flow and increasing the survival of flap zones contralateral to the vascular pedicle (zones III and IV). [ABSTRACT FROM AUTHOR]

Background Extensive degloving injuries of the extremities usually result in necrosis of the flap, necessitating comprehensive skin grafting. Provided there is a sufficient tool to evaluate flap viability, full-thickness skin can be used from a nonviable avulsed flap. We used a Wood's lamp to determine the viability of avulsed flaps in the operation field after intravenous injection of fluorescein dye. Methods We experienced 13 cases during 16 months. Fifteen minutes after the intravenous injection of fluorescein dye, the avulsed skin flaps were examined and non-fluorescent areas were marked under Wood's lamp illumination. The marked area was defatted for full-thickness skin grafting. The fluorescent areas were sutured directly without tension. The non-fluorescent areas were covered by defatted skin. Several days later, there was soft tissue necrosis within the flap area. We measured necrotic area and revised the flap. Results Among all the cases, necrotic area was 21.3% of the total avulsed area. However, if we exclude three cases, one of a carelessly managed patient and two cases of the flaps were inappropriately applied, good results were obtained, with a necrotic area of only 8.4%. Eight patients needed split-thickness skin grafts, and heel pad reconstruction was performed with free flap. Conclusions A full-thickness skin graft from an avulsed flap is a good method for addressing aesthetic concerns without producing donor site morbidity. Fluorescein dye is a useful, simple, and cost-effective tool for evaluating flap viability. Avulsed flap injuries can be managed well with Wood's lamp illumination and a full-thickness skin graft.

Purpose Gross testicular heterogeneity on ultrasound has been associated with testis loss following testicular torsion in children. We aimed to quantify the extent of temporal heterogeneity associated with testis loss in testicular torsion cases using a noninvasive technique to determine a HI (heterogeneity index) on ultrasound images. Materials and Methods We retrospectively studied the records of patients who presented with acute scrotal pain to the Pediatric Emergency Department over a 6-year period. Ultrasound images of the affected testis and the unaffected contralateral testis were examined using a proprietary program to determine the extent of heterogeneity of each image. The difference between the HI of the torsed testis and that of the contralateral normal testis was termed ΔHI. Receiver operating characteristics curve analysis was performed to determine the ΔHI threshold for nonviability. Results Among 529 patients who presented with acute scrotal pain 147 had testicular torsion based on surgical findings. Of these 147 patients 110 (74.8%) were found to have a viable testis while 37 (25.2%) had a nonviable testis. Using the ΔHI cutoff of 0.394 or greater for nonviability, sensitivity and specificity were 100% and 94.5%, respectively. Positive and negative predictive values were 86% and 100%, respectively. Conclusions Our results demonstrate that a quantifiable temporal gradation of heterogeneity exists and the heterogeneity index can be used as an objective parameter to determine the viability of a torsed testicle. By developing the technology to measure the heterogeneity index in real time, we could potentially identify which patients with testicular torsion have a nonviable testicle and, thus, would not require immediate surgical exploration. [ABSTRACT FROM AUTHOR]

Candesartan is a nonpeptide angiotensin II receptor blocker that selectively binds to angiotensin II receptor subtype 1. It is administered orally in its ester form (candesartan cilexetil). However, its poor aqueous solubility results in its low bioavailability; therefore, other routes of administration must be explored. The buccal mucosa has been extensively studied as an alternative route for drug delivery as it improves the bioavailability of drugs administered via the peroral route. Porcine buccal mucosa has been widely used as an ex vivo model to study the permeability of various diffusants; however, studies on candesartan are limited. This study aimed to evaluate the ex vivo permeation profile of candesartan and its effects on the viability and integrity of porcine buccal mucosa. Initially, we evaluated the viability, integrity, and barrier function of the buccal tissue before performing permeability tests using freshly excised tissues or tissues after 12 h of resection. Here, three indicators were used: caffeine, β-estradiol, and FD-20 penetration; mucosal metabolic activity, as determined using MTT reduction assay; and haematoxylin and eosin staining. Our results indicated that the porcine buccal mucosa preserved its viability, integrity, and barrier function before the permeation assay, allowing the passage of molecules with a molecular mass of less than 20 kDa, such as caffeine, but not β-estradiol and FD-20. Furthermore, we analyzed the intrinsic capacity of candesartan to diffuse through the fresh porcine buccal mucosa under two pH conditions. The concentration of candesartan in the receptor chamber of Franz diffusion cell was quantified using ultra-high liquid chromatography. In the permeation assay, candesartan exhibited a low intrinsic permeation capacity that impacted the buccal tissue viability and integrity, suggesting that using the buccal mucosa as an alternative route of administration requires developing a pharmaceutical formulation that reduces the adverse effects on mucosa and increasing the buccal permeability of candesartan., (Copyright © 2023. Published by Elsevier B.V.)