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  1. Article ; Online: Highly stable and immunogenic CMV T cell vaccine candidate developed using a synthetic MVA platform.

    Yll-Pico, Marcal / Park, Yoonsuh / Martinez, Joy / Iniguez, Angelina / Kha, Mindy / Kim, Taehyun / Medrano, Leonard / Nguyen, Vu H / Kaltcheva, Teodora / Dempsey, Shannon / Chiuppesi, Flavia / Wussow, Felix / Diamond, Don J

    NPJ vaccines

    2024  Volume 9, Issue 1, Page(s) 68

    Abstract: Human cytomegalovirus (CMV) is the most common infectious cause of complications post-transplantation, while a CMV vaccine for transplant recipients has yet to be licensed. Triplex, a multiantigen Modified Vaccinia Ankara (MVA)-vectored CMV vaccine ... ...

    Abstract Human cytomegalovirus (CMV) is the most common infectious cause of complications post-transplantation, while a CMV vaccine for transplant recipients has yet to be licensed. Triplex, a multiantigen Modified Vaccinia Ankara (MVA)-vectored CMV vaccine candidate based on the immunodominant antigens phosphoprotein 65 (pp65) and immediate-early 1 and 2 (IE1/2), is in an advanced stage of clinical development. However, its limited genetic and expression stability restricts its potential for large-scale production. Using a recently developed fully synthetic MVA (sMVA) platform, we developed a new generation Triplex vaccine candidate, T10-F10, with different sequence modifications for enhanced vaccine stability. T10-F10 demonstrated genetic and expression stability during extensive virus passaging. In addition, we show that T10-F10 confers comparable immunogenicity to the original Triplex vaccine to elicit antigen-specific T cell responses in HLA-transgenic mice. These results demonstrate improvements in translational vaccine properties of an sMVA-based CMV vaccine candidate designed as a therapeutic treatment for transplant recipients.
    Language English
    Publishing date 2024-03-30
    Publishing country England
    Document type Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-024-00859-3
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  2. Article ; Online: Isolated pancreatic islet yield and quality is inversely related to organ donor age in rats.

    Gonzalez, Nelson / Salgado, Mayra / Medrano, Leonard / Mullen, Yoko / Komatsu, Hirotake

    Experimental gerontology

    2019  Volume 128, Page(s) 110739

    Abstract: Pancreatic islets consist of several endocrine cell types that maintain glucose homeostasis. Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin producing beta cells in pancreatic islets. Islet transplantation is a treatment for ...

    Abstract Pancreatic islets consist of several endocrine cell types that maintain glucose homeostasis. Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin producing beta cells in pancreatic islets. Islet transplantation is a treatment for certain individuals with T1D. Islet transplantation in rodents, as an experimental model of the clinical scenario, requires consistency of islet quantity and quality to obtain reproducible results. In this study, we investigated the yield and function of the isolated islets from rats of different ages. Pancreata were harvested from young (10-20 week-old), intermediate (21-40 week-old) and old (>41 week-old) male rats and islets were isolated using a standard protocol. Islet number, morphometry, viability, function, and metabolism were characterized. Islet yield, normalized to body weight, decreased as a function of increasing donor age. Islets from pancreata from young animals were larger and less fragmented compared to islets from organs from intermediate and older animals. Islet viability following overnight culture was the same for islets derived from young and intermediate aged donors but less for islets from old donors. Glucose-stimulated insulin secretion was decreased in islets from older donors. Islet metabolism following glucose challenge, as measured by oxygen consumption, revealed that islets from old donors were metabolically slower and lagged in response to glucose-stimuli. These data demonstrate that increasing donor age has a negative impact on isolated islet yield and quality.
    MeSH term(s) Age Factors ; Animals ; Body Weight ; Insulin Secretion ; Islets of Langerhans/physiology ; Male ; Oxygen Consumption ; Rats ; Rats, Inbred Lew ; Tissue Donors
    Language English
    Publishing date 2019-10-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 390992-x
    ISSN 1873-6815 ; 0531-5565
    ISSN (online) 1873-6815
    ISSN 0531-5565
    DOI 10.1016/j.exger.2019.110739
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  3. Article: Microwell culture platform maintains viability and mass of human pancreatic islets.

    Kato, Hiroyuki / Miwa, Tatsuaki / Quijano, Janine / Medrano, Leonard / Ortiz, Jose / Desantis, Akiko / Omori, Keiko / Wada, Aya / Tatsukoshi, Kentaro / Kandeel, Fouad / Mullen, Yoko / Ku, Hsun Teresa / Komatsu, Hirotake

    Frontiers in endocrinology

    2022  Volume 13, Page(s) 1015063

    Abstract: Background: Transplantation of the human pancreatic islets is a promising approach for specific types of diabetes to improve glycemic control. Although effective, there are several issues that limit the clinical expansion of this treatment, including ... ...

    Abstract Background: Transplantation of the human pancreatic islets is a promising approach for specific types of diabetes to improve glycemic control. Although effective, there are several issues that limit the clinical expansion of this treatment, including difficulty in maintaining the quality and quantity of isolated human islets prior to transplantation. During the culture, we frequently observe the multiple islets fusing together into large constructs, in which hypoxia-induced cell damage significantly reduces their viability and mass. In this study, we introduce the microwell platform optimized for the human islets to prevent unsolicited fusion, thus maintaining their viability and mass in long-term cultures.
    Method: Human islets are heterogeneous in size; therefore, two different-sized microwells were prepared in a 35 mm-dish format: 140 µm × 300 µm-microwells for <160 µm-islets and 200 µm × 370 µm-microwells for >160 µm-islets. Human islets (2,000 islet equivalent) were filtered through a 160 µm-mesh to prepare two size categories for subsequent two week-cultures in each microwell dish. Conventional flat-bottomed 35 mm-dishes were used for non-filtered islets (2,000 islet equivalent/2 dishes). Post-cultured islets are collected to combine in each condition (microwells and flat) for the comparisons in viability, islet mass, morphology, function and metabolism. Islets from three donors were independently tested.
    Results: The microwell platform prevented islet fusion during culture compared to conventional flat bottom dishes, which improved human islet viability and mass. Islet viability and mass on the microwells were well-maintained and comparable to those in pre-culture, while flat bottom dishes significantly reduced islet viability and mass in two weeks. Morphology assessed by histology, insulin-secreting function and metabolism by oxygen consumption did not exhibit the statistical significance among the three different conditions.
    Conclusion: Microwell-bottomed dishes maintained viability and mass of human islets for two weeks, which is significantly improved when compared to the conventional flat-bottomed dishes.
    MeSH term(s) Humans ; Islets of Langerhans ; Insulin ; Glycemic Control ; Hypoxia ; Oxygen Consumption
    Chemical Substances Insulin
    Language English
    Publishing date 2022-11-17
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2022.1015063
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  4. Article ; Online: Oxygenated thawing and rewarming alleviate rewarming injury of cryopreserved pancreatic islets.

    Komatsu, Hirotake / Barriga, Alyssa / Medrano, Leonard / Omori, Keiko / Kandeel, Fouad / Mullen, Yoko

    Biochemical and biophysical research communications

    2017  Volume 486, Issue 3, Page(s) 817–823

    Abstract: Background/aims: Pancreatic islet transplantation is an effective treatment for Type 1 diabetic patients to eliminate insulin injections; however, a shortage of donor organs hinders the widespread use. Although long-term islet storage, such as ... ...

    Abstract Background/aims: Pancreatic islet transplantation is an effective treatment for Type 1 diabetic patients to eliminate insulin injections; however, a shortage of donor organs hinders the widespread use. Although long-term islet storage, such as cryopreservation, is considered one of the key solutions, transplantation of cryopreserved islets is still not practical due to the extensive loss during the cryopreservation-rewarming process. We have previously reported that culturing islets in a hyperoxic environment is an effective treatment to prevent islet death from the hypoxic injury during culture. In this study, we explored the effectiveness of thawing and rewarming cryopreserved islets in a hyperoxic environment.
    Methods: Following cryopreservation of isolated human islets, the thawing solution and culture media were prepared with or without pre-equilibration to 50% oxygen. Thawing/rewarming and the pursuant two-day culture were performed with or without oxygenation. Short-term recovery rate, defined as the volume change during cryopreservation and thawing/rewarming, was assessed. Ischemia-associated and inflammation-associated gene expressions were examined using qPCR after the initial rewarming period. Long-term recovery rate, defined as the volume change during the two-day culture after the thawing/rewarming, was also examined. Islet metabolism and function were assessed by basal oxygen consumption rate and glucose stimulated insulin secretion after long-term recovery.
    Results: Oxygenated thawing/rewarming did not alter the short-term recovery rate. Inflammation-associated gene expressions were elevated by the conventional thawing/rewarming method and suppressed by the oxygenated thawing/rewarming, whereas ischemia-associated gene expressions did not change between the thawing/rewarming methods. Long-term recovery rate experiments revealed that only the combination therapy of oxygenated thawing/rewarming and oxygenated culture alleviated islet volume loss. These islets showed higher metabolism and better function among the conditions examined.
    Conclusion: Oxygenated thawing/rewarming alleviated islet volume loss, with the help of oxygenated culture.
    MeSH term(s) Cell Survival/drug effects ; Cryopreservation/methods ; Cryoprotective Agents/pharmacology ; Glucose/pharmacology ; Humans ; Insulin/metabolism ; Insulin Secretion ; Islets of Langerhans/cytology ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Islets of Langerhans Transplantation ; Oxygen/pharmacology ; Primary Cell Culture ; Rewarming/methods
    Chemical Substances Cryoprotective Agents ; Insulin ; Glucose (IY9XDZ35W2) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2017-03-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 205723-2
    ISSN 1090-2104 ; 0006-291X ; 0006-291X
    ISSN (online) 1090-2104 ; 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2017.03.134
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  5. Article ; Online: A Multiparametric Assessment of Human Islets Predicts Transplant Outcomes in Diabetic Mice.

    Komatsu, Hirotake / Qi, Meirigeng / Gonzalez, Nelson / Salgado, Mayra / Medrano, Leonard / Rawson, Jeffrey / Orr, Chris / Omori, Keiko / Isenberg, Jeffrey S / Kandeel, Fouad / Mullen, Yoko / Al-Abdullah, Ismail H

    Cell transplantation

    2021  Volume 30, Page(s) 9636897211052291

    Abstract: Prior to transplantation into individuals with type 1 diabetes, in vitro assays are used to evaluate the quality, function and survival of isolated human islets. In addition to the assessments of these parameters in islet, they can be evaluated by ... ...

    Abstract Prior to transplantation into individuals with type 1 diabetes, in vitro assays are used to evaluate the quality, function and survival of isolated human islets. In addition to the assessments of these parameters in islet, they can be evaluated by multiparametric morphological scoring (0-10 points) and grading (A, B, C, D, and F) based on islet characteristics (shape, border, integrity, single cells, and diameter). However, correlation between the multiparametric assessment and transplantation outcome has not been fully elucidated. In this study, 55 human islet isolations were scored using this multiparametric assessment. The results were correlated with outcomes after transplantation into immunodeficient diabetic mice. In addition, the multiparametric assessment was compared with oxygen consumption rate of isolated islets as a potential prediction factor for successful transplantations. All islet batches were assessed and found to score: 9 points (
    MeSH term(s) Animals ; Diabetes Mellitus, Experimental/physiopathology ; Diabetes Mellitus, Type 1/physiopathology ; Humans ; Islets of Langerhans Transplantation/methods ; Mice ; Mice, SCID ; Retrospective Studies ; Treatment Outcome
    Language English
    Publishing date 2021-10-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1135816-6
    ISSN 1555-3892 ; 0963-6897
    ISSN (online) 1555-3892
    ISSN 0963-6897
    DOI 10.1177/09636897211052291
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  6. Article ; Online: High Fractions of Large Islets in Human Islet Preparations Detrimentally Affect Posttransplant Outcomes in Streptozotocin-Induced Diabetic Immunodeficient Mice.

    Komatsu, Hirotake / Salgado, Mayra / Gonzalez, Nelson / Medrano, Leonard / Rawson, Jeffrey / Omori, Keiko / Qi, Meirigeng / Al-Abdullah, Ismail / Kandeel, Fouad / Mullen, Yoko

    Pancreas

    2020  Volume 49, Issue 5, Page(s) 650–654

    Abstract: Objectives: The aim of this study was to determine whether the size of islets isolated from human donors-measured pretransplant-impacts transplantation outcomes in diabetic mice.: Methods: Human islets (1200 islet equivalents) were transplanted into ... ...

    Abstract Objectives: The aim of this study was to determine whether the size of islets isolated from human donors-measured pretransplant-impacts transplantation outcomes in diabetic mice.
    Methods: Human islets (1200 islet equivalents) were transplanted into the kidney capsules of streptozotocin-induced diabetic immunodeficient mice. Data from a total of 174 mice that received islets from 45 isolations were analyzed to evaluate the correlation between pretransplant islet size and posttransplant diabetes reversal. Fluorescent images of islet clusters were used to categorize individual islets by size (small, 50-150 μm; medium, 150-250 μm; large, >250 μm), and the fractions of islets in each category were calculated.
    Results: The fraction of large islets negatively correlated with diabetes reversal rates. Mice that received islet grafts containing 0% to 5%, 5% to 10%, and more than 10% large islets had diabetes reversal rates of 75%, 61%, and 45%, respectively (P = 0.0112). Furthermore, mice that exhibited diabetes reversal received smaller fractions of large islets than mice that did not (5.5% vs 8.0%, P = 0.0003). Intriguingly, the fractions of medium and small islets did not correlate with diabetes reversal outcomes.
    Conclusions: The fraction of large islets is a sensitive predictor of human islet transplantation outcomes in diabetic mice.
    MeSH term(s) Animals ; Diabetes Mellitus, Experimental/surgery ; Graft Survival/physiology ; Humans ; Islets of Langerhans/physiology ; Islets of Langerhans Transplantation/methods ; Mice, Inbred NOD ; Mice, SCID ; Outcome Assessment, Health Care ; Retrospective Studies ; Transplantation, Heterologous
    Language English
    Publishing date 2020-06-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632831-3
    ISSN 1536-4828 ; 0885-3177
    ISSN (online) 1536-4828
    ISSN 0885-3177
    DOI 10.1097/MPA.0000000000001541
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  7. Article ; Online: Semi-Automated Assessment of Human Islet Viability Predicts Transplantation Outcomes in a Diabetic Mouse Model.

    Salgado, Mayra / Gonzalez, Nelson / Medrano, Leonard / Rawson, Jeffrey / Omori, Keiko / Qi, Meirigeng / Al-Abdullah, Ismail / Kandeel, Fouad / Mullen, Yoko / Komatsu, Hirotake

    Cell transplantation

    2020  Volume 29, Page(s) 963689720919444

    Abstract: In clinical and experimental human pancreatic islet transplantations, establishing pretransplant assessments that accurately predict transplantation outcomes is crucial. ... ...

    Abstract In clinical and experimental human pancreatic islet transplantations, establishing pretransplant assessments that accurately predict transplantation outcomes is crucial. Conventional
    MeSH term(s) Animals ; Diabetes Mellitus, Experimental/therapy ; Disease Models, Animal ; Humans ; Islets of Langerhans Transplantation/methods ; Male ; Mice ; Treatment Outcome
    Language English
    Publishing date 2020-06-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1135816-6
    ISSN 1555-3892 ; 0963-6897
    ISSN (online) 1555-3892
    ISSN 0963-6897
    DOI 10.1177/0963689720919444
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  8. Article ; Online: Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival.

    Komatsu, Hirotake / Cook, Colin / Wang, Chia-Hao / Medrano, Leonard / Lin, Henry / Kandeel, Fouad / Tai, Yu-Chong / Mullen, Yoko

    PloS one

    2017  Volume 12, Issue 8, Page(s) e0183780

    Abstract: Background: Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including ... ...

    Abstract Background: Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including donor shortage, prevention of islet necrosis and loss in pre- and post-transplantation, and optimization of immunosuppression. This study seeks to determine the cause of necrotic loss of isolated islets to improve transplant efficiency.
    Methodology: The oxygen tension inside isolated human islets of different sizes was simulated under varying oxygen environments using a computational in silico model. In vitro human islet viability was also assessed after culturing in different oxygen conditions. Correlation between simulation data and experimentally measured islet viability was examined. Using these in vitro viability data of human islets, the effect of islet diameter and oxygen tension of the culture environment on islet viability was also analyzed using a logistic regression model.
    Principal findings: Computational simulation clearly revealed the oxygen gradient inside the islet structure. We found that oxygen tension in the islet core was greatly lower (hypoxic) than that on the islet surface due to the oxygen consumption by the cells. The hypoxic core was expanded in the larger islets or in lower oxygen cultures. These findings were consistent with results from in vitro islet viability assays that measured central necrosis in the islet core, indicating that hypoxia is one of the major causes of central necrosis. The logistic regression analysis revealed a negative effect of large islet and low oxygen culture on islet survival.
    Conclusions/significance: Hypoxic core conditions, induced by the oxygen gradient inside islets, contribute to the development of central necrosis of human isolated islets. Supplying sufficient oxygen during culture could be an effective and reasonable method to maintain isolated islets viable.
    MeSH term(s) Cell Survival ; Humans ; Islets of Langerhans/metabolism ; Logistic Models ; Oxygen/metabolism ; Oxygen Consumption
    Chemical Substances Oxygen (S88TT14065)
    Language English
    Publishing date 2017
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0183780
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  9. Article ; Online: Optimizing Temperature and Oxygen Supports Long-term Culture of Human Islets.

    Komatsu, Hirotake / Rawson, Jeffrey / Medrano, Leonard / Cook, Colin A / Barriga, Alyssa / Gonzalez, Nelson / Salgado, Mayra / Omori, Keiko / Kandeel, Fouad / Tai, Yu-Chong / Mullen, Yoko

    Transplantation

    2018  Volume 103, Issue 2, Page(s) 299–306

    Abstract: Islet transplantation is a promising treatment for type-1 diabetes; however, donor shortage is a concern. Even when a pancreas is available, low islet yield limits the success of transplantation. Islet culture enables pooling of multiple low-yield ... ...

    Abstract Islet transplantation is a promising treatment for type-1 diabetes; however, donor shortage is a concern. Even when a pancreas is available, low islet yield limits the success of transplantation. Islet culture enables pooling of multiple low-yield isolations into an effective islet mass, but isolated islets rapidly deteriorate under conventional culture conditions. Oxygen (O2) depletion in the islet core, which leads to central necrosis and volume loss, is one of the major reasons for this deterioration.
    Methods: To promote long-term culture of human islets in PIM-R medium (used for islet research), we adjusted temperature (12°C, 22°C, and 37°C) and O2 concentration (21% and 50%). We simulated the O2 distribution in islets based on islet O2 consumption rate and dissolved O2 in the medium. We determined the optimal conditions for O2 distribution and volume maintenance in a 2-week culture and assessed viability and insulin secretion compared to noncultured islets. In vivo islet engraftment was assessed by transplantation into diabetic nonobese diabetic-severe combined immunodeficiency mouse kidneys. We validated our results using CMRL 1066 medium (used for clinical islet transplantation).
    Results: Simulation revealed that 12°C of 50% O2 PIM-R culture supplied O2 effectively into the islet core. This condition maintained islet volume at greater than 90% for 2 weeks. There were no significant differences in viability and function in vitro or diabetic reversal rate in vivo between 2-week cultured and noncultured islets. Similar results were obtained using CMRL 1066.
    Conclusions: By optimizing temperature and O2 concentration, we cultured human islets for 2 weeks with minimal loss of volume and function.
    MeSH term(s) Adenosine Triphosphate/pharmacology ; Animals ; Cell Culture Techniques/methods ; Culture Media ; Humans ; Islets of Langerhans/cytology ; Islets of Langerhans/physiology ; Mice ; Oxygen/pharmacology ; Temperature
    Chemical Substances Culture Media ; Adenosine Triphosphate (8L70Q75FXE) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2018-06-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 208424-7
    ISSN 1534-6080 ; 0041-1337
    ISSN (online) 1534-6080
    ISSN 0041-1337
    DOI 10.1097/TP.0000000000002280
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  10. Article ; Online: Evaluation of collagenase gold plus BP protease in isolating islets from human pancreata.

    Khiatah, Bashar / Tucker, Amber / Chen, Kuan-Tsen / Perez, Rachel / Bilbao, Shiela / Valiente, Luis / Medrano, Leonard / Rawson, Jeffrey / Forouhar, Elena / Omori, Keiko / Kandeel, Fouad / Qi, Meirigeng / Al-Abdullah, Ismail H

    Islets

    2018  Volume 10, Issue 2, Page(s) 51–59

    Abstract: Selection of enzymes for optimal pancreas digestion is essential for successful human islet isolations. The aim of this study was to evaluate the efficacy and outcome of using Collagenase Gold plus BP protease (VitaCyte) (n = 8) by comparing it to two ... ...

    Abstract Selection of enzymes for optimal pancreas digestion is essential for successful human islet isolations. The aim of this study was to evaluate the efficacy and outcome of using Collagenase Gold plus BP protease (VitaCyte) (n = 8) by comparing it to two commercially available enzymes, Liberase MTF C/T (Roche) (n = 48) and Collagenase NB1/NP (Serva) (n = 15). The isolation outcomes were assessed by islet counting, viability, glucose-stimulated oxygen consumption rate (OCR), and successful graft-rate following transplantation in diabetic NOD scid mice. The pancreas donor characteristics were not significantly different between the tested enzyme groups regarding their BMI, pancreas weight, cold ischemia time (CIT) and HbA1c. The results show that digested tissue volume was not statistically significant between the VitaCyte enzyme (34.25 ± 5.4 mL) and the Roche enzyme (55.25 ± 3.42 mL, p = 0.073), however, this was significant with Serva enzyme (64.07 ± 7.95 mL, p = 0.020). Interestingly, the islet yields were not statistically different between all enzyme groups. Moreover, when islets were transplanted into NOD scid mice, the reversal rate of diabetes for the VitaCyte enzyme group was similar to all enzyme groups. In conclusion, the effectiveness of Collagenase Gold plus BP protease is comparable to the MTF C/T and the Collagenase NB1/NP enzymes; the low cost could facilitate the use of more pancreata for islet isolations.
    MeSH term(s) Adult ; Animals ; Cell Separation/methods ; Cell Survival ; Collagenases ; Graft Survival ; Humans ; Islets of Langerhans/cytology ; Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Middle Aged ; Oxygen Consumption ; Peptide Hydrolases ; Retrospective Studies ; Thermolysin ; Young Adult
    Chemical Substances Peptide Hydrolases (EC 3.4.-) ; Collagenases (EC 3.4.24.-) ; Liberase (EC 3.4.24.-) ; Thermolysin (EC 3.4.24.27)
    Language English
    Publishing date 2018-02-02
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1938-2022
    ISSN (online) 1938-2022
    DOI 10.1080/19382014.2017.1417716
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