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Friberg, Andrew S
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Publications (9 of 9) Show all publications
Brandhorst, D., Parnaud, G., Friberg, A., Lavallard, V., Demuylder-Mischler, S., Hughes, S., . . . Johnson, P. R. V. (2017). Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation. Cell Transplantation, 26(10), 1688-1693
Open this publication in new window or tab >>Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation
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2017 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 10, p. 1688-1693Article in journal (Refereed) Published
Abstract [en]

Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000-2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean +/- standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 +/- 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 +/- 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 +/- 33,620 islet equivalents (IEQ) equivalent to 3,274 +/- 450 IEQ/g with a purity of 55.9% +/- 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% +/- 1.5% and a stimulation index of 3.7 +/- 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 +/- 0.08 pretransplant to 1.23 +/- 0.24 and 2.27 +/- 0.31 ng/mL 3 and 6 mo posttransplant (P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 +/- 3.8 IU/d before transplantation to 10.8 +/- 4.1 and 4.0 +/- 2.3 IU/d, after 3 and 6 mo posttransplant (P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field.

Place, publisher, year, edition, pages
Sage Publications, 2017
Keywords
human islet isolation, human islet transplantation, collagenase, islet quality assessment
National Category
Endocrinology and Diabetes Cell Biology
Identifiers
urn:nbn:se:uu:diva-339724 (URN)10.1177/0963689717731574 (DOI)000418298500008 ()29251107 (PubMedID)
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-01-22Bibliographically approved
Ståhle, M., Foss, A., Gustafsson, B., Lempinen, M., Lundgren, T., Rafael, E., . . . Friberg, A. (2016). Evaluation of Perfluorohexyloctane/Polydimethylsiloxane for Pancreas Preservation for Clinical Islet Isolation and Transplantation. Cell Transplantation, 25(12), 2269-2276
Open this publication in new window or tab >>Evaluation of Perfluorohexyloctane/Polydimethylsiloxane for Pancreas Preservation for Clinical Islet Isolation and Transplantation
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2016 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 25, no 12, p. 2269-2276Article in journal (Refereed) Published
Abstract [en]

This study aimed to evaluate a 50:50 mix of perfluorohexyloctane/polydimethylsiloxane 5 (F6H8S5) preservation of pancreases in a clinical setting compared with standard solutions for 1) cold ischemia time (CIT) <10 h and 2) an extended CIT >20 h. Procured clinical-grade pancreases were shipped in either F6H8S5 or in standard preservation solutions, that is, University of Wisconsin (UW) or Custodiol. F6H5S5 was preoxygenated for at least 15 min. Included clinical-grade pancreases were procured in UW or Custodiol. Upon arrival at the islet isolation laboratory, the duodenum was removed followed by rough trimming while F6H8S5 was oxygenated for 15-20 min. Trimmed pancreases were immersed into oxygenated F6H8S5 and stored at 4 C overnight followed by subsequent islet isolation. Pancreas preservation using F6H8S5 proved as effective as UW and Custadiol when used within CIT up to 10 h, in terms of both isolation outcome and islet functionality. Preservation in F6H8S5 of pancreases with extended CIT gave results similar to controls with CIT <10 h for both isolated islet functionality and isolation outcome. This study of clinically obtained pancreases indicates a clear benefit of using F6H8S5 on pancreases with extended CIT as it seems to allow extended cold ischemic time without affecting islet function and islet numbers.

Keywords
Islet isolation, Pancreas preservation, Clinical islet transplantation, Perfluorohydrocarbons, Oxygenation, Hypoxia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-313431 (URN)10.3727/096368916X691709 (DOI)000390183200014 ()
Funder
Swedish Research Council, K2015-54X-12219-19-4Swedish Child Diabetes FoundationSwedish Diabetes AssociationNIH (National Institute of Health), 2U01AI065192-06EXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2017-01-30 Created: 2017-01-19 Last updated: 2017-11-29Bibliographically approved
Ricordi, C., Goldstein, J. S., Balamurugan, A. N., Szot, G. L., Kin, T., Liu, C., . . . Shapiro, A. M. (2016). National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. Diabetes, 65(11), 3418-3428
Open this publication in new window or tab >>National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities
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2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 11, p. 3418-3428Article in journal (Refereed) Published
Abstract [en]

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-308901 (URN)10.2337/db16-0234 (DOI)000386538500020 ()
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2017-11-29Bibliographically approved
Goto, M., Friberg, A., Ståhle, M., Imura, T., Yamagata, Y., Watanabe, K., . . . Korsgren, O. (2015). Proof of concept for the clinical application of animal component free recombinant collagenase for isolating pancreatic islets. Paper presented at IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA. Xenotransplantation, 22, S50-S50
Open this publication in new window or tab >>Proof of concept for the clinical application of animal component free recombinant collagenase for isolating pancreatic islets
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2015 (English)In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S50-S50Article in journal, Meeting abstract (Other academic) Published
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-276044 (URN)000364594100117 ()
Conference
IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-02-09 Created: 2016-02-09 Last updated: 2017-11-30Bibliographically approved
Goto, M., Friberg, A., Ståhle, M., Imura, T., Yamagata, Y., Watanabe, K., . . . Korsgren, O. (2015). Proof Of Concept For The Clinical Application Of Animal Component Free Recombinant Collagenase For Isolating Pancreatic Islets. Paper presented at Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA. Transplantation, 99(11), S80-S80
Open this publication in new window or tab >>Proof Of Concept For The Clinical Application Of Animal Component Free Recombinant Collagenase For Isolating Pancreatic Islets
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2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S80-S80Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-281551 (URN)000368625700114 ()
Conference
Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-04-05 Created: 2016-03-24 Last updated: 2018-01-10Bibliographically approved
Ståhle, M., Honkanen-Scott, M., Ingvast, S., Korsgren, O. & Friberg, A. S. (2013). Human islet isolation processing times shortened by one hour: minimized incubation time between tissue harvest and islet purification [Letter to the editor]. Transplantation, 96(12), e91-e93
Open this publication in new window or tab >>Human islet isolation processing times shortened by one hour: minimized incubation time between tissue harvest and islet purification
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2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 12, p. e91-e93Article in journal, Letter (Refereed) Published
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-274641 (URN)10.1097/01.TP.0000437562.31212.d5 (DOI)24342944 (PubMedID)
Available from: 2016-01-25 Created: 2016-01-25 Last updated: 2017-11-30Bibliographically approved
Friberg, A. S., Lundgren, T., Malm, H., Felldin, M., Nilsson, B., Jenssen, T., . . . Korsgren, O. (2012). Transplanted functional islet mass: donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients. Transplantation, 93(6), 632-638
Open this publication in new window or tab >>Transplanted functional islet mass: donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients
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2012 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 6, p. 632-638Article in journal (Refereed) Published
Abstract [en]

Background.

The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.

Methods.

Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).

Results.

Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.

Conclusion.

The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

Keywords
Islet transplantation, Pretransplant evaluation, Transplant outcome, Prediction, Islet-After-Kidney
National Category
Surgery Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-170920 (URN)10.1097/TP.0b013e3182455912 (DOI)000301350100014 ()22258287 (PubMedID)
Funder
Swedish Research Council, K2011-65X-12219-15-6NIH (National Institute of Health), 2U01AI065192-06Swedish Childhood Cancer Foundation
Available from: 2012-03-13 Created: 2012-03-13 Last updated: 2018-01-12Bibliographically approved
Friberg, A. S. (2011). Standardization of Islet Isolation and Transplantation Variables. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Standardization of Islet Isolation and Transplantation Variables
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Currently, the transplantation of islets of Langerhans is a viable means to maintain control of blood sugar levels and reduce the risk of hypoglycemia in defined populations with brittle type I diabetes mellitus or those requiring pancreatectomy. However, the process of islet isolation is highly variable and not all isolations result in islet numbers or quality suitable for transplantation.

This thesis aimed to improve transplantation success through optimization and standardization of the isolation process and to identify pretransplant variables associated with early islet engraftment.

A previously disregarded enzyme activity, tryptic-like activity (TLA), has been identified to influence pancreas digestion efficiency and islet isolation success in both the preclinical and clinical situations. For human pancreases, islet isolation success rates improved from 0% in the lowest TLA group to over 50% in the highest TLA groups without affecting islet quality. These findings should help standardize evaluation of enzymes for clinical islet isolation.

A closed, automated, pump-made gradient system was compared to the open, manual method for islet separation. No differences were observed in expected gradient volumes, islet yields or total purities between the two methods. The pump-made gradient system successfully removed manual influences on density gradient production while fulfilling regulatory requirements for closed system processing.

Islet quantification was evaluated with computer-assisted digital imaging analysis (DIA) and a semi-closed assessment system. By using the DIA system method, which measures islet purity and pellet volume instead of manual counting methods, variation in islet counts and purity reduced by almost half.

By using a transplant outcome measurement of C-peptide adjusted by blood glucose and creatinine, we identified four pretransplant factors that affect early transplant outcome. Of the four factors, one was related to the organ transport time, one to function of the islets, and two to the transplanted tissue volume. When these four factors were put into a predictive model, it accounted for about 40% of the transplant outcome.

The work contained in this thesis identifies and optimizes a number of critical elements related to islet isolation and transplantation protocols.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 669
Keywords
Islet isolation, standardization, enzyme, gradient separation, digital imaging analysis, DIA, transplantation outcome, islet transplantation, prediction
National Category
Biomedical Laboratory Science/Technology
Research subject
Medical Cell Biology; Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-150247 (URN)978-91-554-8066-0 (ISBN)
Public defence
2011-05-23, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-05-02 Created: 2011-03-28 Last updated: 2011-07-01Bibliographically approved
Friberg, A. S., Lundgren, T., Malm, H., Felldin, M., Nilsson, B., Jensson, T., . . . Korsgren, O.Transplantable functional islet mass – predictive biomarkers of graft function in islet after kidney transplanted patients.
Open this publication in new window or tab >>Transplantable functional islet mass – predictive biomarkers of graft function in islet after kidney transplanted patients
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. Analysis of donor, islet isolation, quality control and recipient variables was undertaken in 110 islet after kidney (IAK) transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr). Using backward multiple regression the variables positively associated to ΔCP/GCr were islet volume transplanted (p<0.001) and glucose stimulated insulin secretion (SI) (p=0.009). Factors negatively associated to ΔCP/GCr were cold ischemia time (CIT) (p=0.002) and total tissue volume (p=0.009). Donor age, donor body mass index, number of retrieved organs from the donor, preservation solution, islet insulin content, body weight of the recipient of the islets had no influence on transplant function. The transplantable functional islet mass (TFIM), accounting for islet volume transplanted, SI, CIT, and total tissue volume explained 39% of the variance of the clinical outcome in the IAK data set. Therefore, the TFIM provides a straightforward and potent tool to guide the decision to utilize a specific islet preparation for clinical transplantation.

Keywords
Islet transplantation, kidney function, predict outcome, transplantable islet mass
National Category
Surgery
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-150243 (URN)
Available from: 2011-03-28 Created: 2011-03-28 Last updated: 2015-06-16
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