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P Soon-Shiong

Publications and source records attributed to P Soon-Shiong.

At least 19 recordsLinked to original sources
PubMed1999

Molecular mass distribution of sodium alginate by high-performance size-exclusion chromatography.

A sensitive high-performance size-exclusion chromatography (HPSEC) method with simple UV detection was developed for the molecular mass analysis of sodium alginate. It was used to evaluate alginates of varying molecular mass and the results were compared with the viscosity measurements. This HPSEC method was sensitive to serve as the stability indicating method for alginate after storage under different conditions. The information of relative molecular mass distribution of alginate was provided with reference to pullulan molecular mass standards. The comparison of the HPSEC chromatograms of alginate, pullulan and dextran revealed the effect of chemical composition of a polysaccharide and its effect on apparent molecular mass distribution.

Alginates↗
PubMed1999

Treatment of type I diabetes using encapsulated islets.

Immune rejection following transplantation of non-encapsulated pancreatic islets has remained a major obstacle to successful treatment of type I diabetes, despite the use of high-dose immunosuppressive drugs with their potentially severe side-effects. Encapsulation circumvents the need for immunosuppression because the transplanted living cells are surrounded by a semipermeable membrane which protects them from the host's immune system. Unfortunately, clinical applications of early encapsulation devices were hampered by their mechanical fragility, their limited surface area, and their need for a major surgical procedure. Although new microencapsulation technologies dispense with many of these issues, not all semipermeable membranes can form a biocompatible and mechanically stable immunoprotective system which allows sufficient oxygenation of the cells as well as adequate insulin diffusion. Alginate-polylysine spherical-bead microcapsules (with improved biocompatibility, mechanical strength, and chemical stability) can now provide a large surface area, enhanced nutrition and oxygen supply, precisely tailored porosity (to discriminate nutrients from immunoglobulins), maximum protection from membrane failure, and direct injectability into the peritoneal cavity. Our objective was to test the therapeutic effectiveness of alginate-polylysine microcapsules for the transplantation of human-insulin-producing cells into a human diabetic patient, a 38-year-old white male with insulin-dependent diabetes for 30 years. Encapsulated islets (10,000 islets/kg) were injected directly into the peritoneal cavity through a 2 cm midline incision. Insulin secretion from the transplanted cells was detected within 24 h after injection, and has continued for more than 58 months. The patient reported significant improvement in the quality of his life including a decrease in his lower extremity peripheral neuropathy symptoms, an increased energy level, an ability to walk further, a general feeling of improved health, and no adverse effects.

Journal Article↗
PubMed1996

Alginate polycation microcapsules. I. Interaction between alginate and polycation.

The interactions between alginate and polycations have been studied by using different labelling techniques. Binding of poly-L-lysine (PLL) to alginate in the gel state is mainly governed by the amount of dissociable negative charges on the bead surface. PLL was found to bind more rapidly to gel beads made from alginate with a high content of mannuronic acid. The binding was enhanced by increasing the alginate concentration on the surface by making inhomogeneous beads. When the capsules were stored in the presence of cations with high affinity for alginate (Ca2+, Sr2+), PLL was washed off. Less PLL is bound to strontium alginate than to calcium alginate beads. Two mechanisms appear to be responsible for the binding of sodium alginate to alginate PLL capsules (coating): (i) an electrostatic interaction between the soluble coating material and excess positive charges on PLL on the surface; (ii) the formation of a calcium alginate gel on the surface owing to leaching of calcium ions from the core. The stability and efficiency of the coating as a function of molecular size and sequential structure of the coating polymer have also been investigated.

Alginates↗
PubMed1996

Alginate polycation microcapsules. II. Some functional properties.

The main cause of alginate polycation capsule breakage under physiological conditions is probably the osmotic swelling of the alginate core owing to the Donnan equilibrium set up by the negative charges of the carboxyl groups not involved in cooperative binding of counterions in the junction zones of the network. In the present paper we show how capsules can be stabilized extensively by reducing their swelling capacity in various ways. Alginate polycation capsules with good chemical and mechanical stability have been made by controlling their swelling behaviour through selection of capsule material according to chemical structure and molecular weight, as well as by controlling the kinetics of the capsule formation. Stable capsules have been made either by increasing the strength of the polyanion-polycation membrane, or by keeping a low-swelling gel network in the core. The latter capsules are made from an alginate rich in guluronic acid both in the core and in an outer coating, and with anisotropic distribution of the polymer material in the core where the concentration at the surface is higher than that in the centre of the capsule. Some functional properties of these capsules, such as porosity, have also been studied.

Alginates↗
PubMed1994

Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation.

Identification of a biocompatible immunoprotective membrane to prevent graft rejection remained elusive until the development of microcapsules formulated in alginate high in guluronic acid. We report insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Encapsulated human islets were injected intraperitoneally in a diabetic patient with a functioning kidney graft. Insulin independence with tight glycaemic control was demonstrated 9 months after the procedure. These results warrant a trial of a high dose of encapsulated islets in early-onset diabetic patients.

Adult↗
PubMed1993

Long-term reversal of diabetes by the injection of immunoprotected islets.

The intraperitoneal injection of insulin-producing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Previous attempts to demonstrate this technology in large animals have failed, preventing application in humans. We have determined that key factors responsible for these past failures include cytokine (interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibroblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontaneous diabetic dog model by the intraperitoneal injection of encapsulated canine islet allografts. Euglycemia, independent of any exogenous insulin requirement, was noted for up to 172 days. Graft survival, evidenced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immunoprotective nature of this capsule formulation. The finding that intraperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (> 1 year) maintenance of glycemic control, without the need for lifelong immunosuppression, may have significant implications for the future therapy of type I diabetes in humans.

Alginates↗
PubMed1992

Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets.

Long-term euglycemia by intraperitoneal transplantation of microencapsulated islets has not been described in the diabetic large animal model. In this study, we report the successful long-term reversal of diabetes by this method in spontaneous diabetic dogs. We have identified fundamental mechanism(s) associated with alginate-based microcapsule fibrosis, and have devised methods to ameliorate this problem. These include the use of purified alginate of low mannuronic acid content and cytokine suppression. Ten insulin-dependent, spontaneous diabetic dogs (insulin requirement 1-4 units/kg/day; absence of circulating C-peptide and diabetic K-values of 0.6 +/- 0.4) were entered into the study. Islets from mongrel donor pancreata were isolated and transplanted intraperitoneally either as free islet controls (n = 3) or as microencapsulated islet allografts (n = 7). In all seven encapsulated islet recipients, euglycemia was achieved within 24 hr (serum glucose failing from 304 +/- 117 to 116 +/- 72 mg/dl). IVGTT performed 14 days after islet transplant demonstrated normalization of K-values changing from a pretransplant level of 0.6 +/- 0.4 to 2.6 +/- 0.6. All animals receiving encapsulated islets remained euglycemic, free of the need for exogenous insulin, for a period of 63-172 days, with a median insulin-independence for 105 days. In contrast, recipients receiving free islets rejected their graft within seven days of implantation. In conclusion, this is the first report of long-term successful reversal of spontaneous diabetes in the large animal model by an intraperitoneal injection of encapsulated islets. The potential exists for this form of therapy to be explored in the treatment of type I diabetes in man.

Animals↗
PubMed1992

Early markers of pancreas transplant rejection.

To compare the predictive value of urinary amylase (UA), urinary insulin (UI), and urinary prostaglandin (PGE2), whole pancreas isografts or allografts from (ACI rat donors, RT1a) with bladder drainage of exocrine secretions were performed in Lewis rats (RT1(1)) with streptozotocin-induced diabetes. UA, UI, PGE2 and plasma glucose levels were measured daily. Euglycemia was restored on Postoperative Day 1 in all the recipients of isografts (N = 6) and was maintained for over a year. UI concentrations and PGE2 outputs were stable, with low levels ranging between 0.3 +/- 0.2 to 7 +/- 2 ng/ml and 56 +/- 15 to 164 +/- 48 ng/24 hr, respectively, while UA levels were significantly elevated compared to normal controls (> 1,000 U/ml vs 29 +/- 16 U/ml). In the allograft group (N = 12), rejection occurred on Days 7 through 9, with a mean graft survival time of 8.1 +/- 0.1 days. UA dropped from a post-transplant peak of 2,422 +/- 353 U/ml on Postoperative Day 4 to below 1,380 +/- 256 U/ml 3 days before rejection (Day -3). UI increased to 83 +/- 16 ng/ml (P < 0.05) on Day -6 and reached a post-transplant peak of 140 +/- 24 ng/ml on Day -5, while PGE2 output rose from a pretransplant level of 18 +/- 2 to 92 +/- 25 ng/24 hr on Postoperative Day 1, followed by a significant elevation on Day 4 (-4).(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1991

Pancreas function index: an early monitor of allograft rejection.

The lack of reliable markers for the early diagnosis of allograft rejection is a major obstacle preventing improved results in clinical pancreas transplantation. Using a vascularized whole-pancreas transplant model in the rat, with exocrine ductal drainage into the lower urinary tract, we explored the possibility that a change in an index of pancreatic function (IPF), viz., urine volume, urine pH, and urine amylase (UA) in composite, may provide an earlier and more specific indicator of rejection than a decline in UA levels alone. Six Lewis-to-Lewis rat isograft and 12 ACI-to-Lewis allograft recipients were studied. Ten nontransplanted diabetic Lewis rats served as a control group. Euglycemia was restored in all the recipients of isografts, and was maintained for over a year. In the allograft group, rejection occurred on Days 7-9, with a mean graft survival time of 8.1 +/- 0.1 days. Peak UA levels and IPF during normal allograft function were 2422 +/- 353 U/ml and 100 +/- 14, respectively, whereas levels heralding rejection were 600 U/ml and 25 (P less than 0.05). The diagnosis of rejection based on the IPF resulted in significantly greater specificity and an earlier prediction time compared with UA alone (2.4 +/- 0.3 vs 1.6 +/- 0.2 days); the IPF permitted the successful prediction of rejection 3 or more days prior to hyperglycemia in 6 of 12 (50%) grafts, whereas only 1 of 12 (8%) rejection episodes was successfully predicted when the rejection criterion was based on UA. In conclusion, early diagnosis of rejection was achieved by a composite index of pancreatic function, improving the ability to predict pancreas-allograft rejection 24 to 48 hr prior to a fall in UA levels.

Amylases↗
PubMed1991

Induction of cytokine production from human monocytes stimulated with alginate.

Alginates are polysaccharides with gel-forming properties composed of 1,4-linked beta-D-mannuronic acid (M), alpha-L-guluronic acid (G), and alternating (MG) blocks. Alginate can be used as a matrix for implanted cells in vivo. In this study, we have examined the ability of alginates and their components to stimulate human monocytes to produce tumor necrosis factor-alpha, interleukin-6, and interleukin-1. Alginates stimulated the monocytes to produce high levels of all three cytokines. Low G alginates were approximately 10 times more potent in inducing cytokine production compared with high G alginates. The M-blocks and the MG-blocks, but not the G-blocks, stimulated the cytokine production. The results demonstrate that the mannuronic acid residues are the active cytokine inducers in alginates.

Alginates↗
PubMed1991

Immunocytochemical identification of monoclonal antibodies with binding activity to acinar cells but not islets.

The development of techniques for separating islets from acinar cells on a mass scale is a prerequisite to successful clinical attempts at islet transplantation. We have identified and partially characterized two blood group-reactive monoclonal antibodies (McAb), CAC1 and CAC2, with specific binding activity to acinar cells but not islets. These McAb are of the IgM subclass, and were found on immunocytochemical analysis to possess broad interspecies cross-reactivity, binding to antigens expressed in the acinar tissue of rats, dogs, and man. The antigens that these McAb recognize are glycolipid in nature and thus were not denatured by collagenase digestion of the pancreas. These properties, together with their ability to effect complement-mediated lysis, may make the McAb generally useful reagents in islet isolation and purification.

ABO Blood-Group System↗
PubMed1991

Prolonged pancreas preservation using a simplified UW solution containing polyethylene glycol.

The University of Wisconsin solution is considered the most effective universal flush and cold storage solution to date, and is now being widely applied clinically in organ transplantation. The results of this study show that Cardiosol, a modified cardioplegic solution containing 5% polyethylene glycol (PEG20M, MW 17,000 daltons), is significantly superior to UW (P less than 0.001) in the flush perfusion and hypothermic storage of pancreases for more than 36 hr prior to transplantation into streptozotocin-induced diabetic rats. When the pancreases were stored in Cardiosol, the 1-week survival rate was 7 of 10 (70%) after 24 hr of preservation; 7 of 12 (58%) after 36 hr; and 3 of 10 (30%) after 48 hr. In contrast, when the pancreases were stored in UW solution, the 1-week survival rate was 8 of 12 (67%) after 24 hr of preservation; after 36 hr, no animal survived (0 of 14). Intravenous glucose tolerance test K-values (decline in glucose concentration, percentage per minute) were normal in both groups receiving 24-hr-preserved pancreases, ranging from 2.60 to 4.16. Of interest, the peak insulin response 1 min following intravenous glucose was significantly higher (P less than 0.01) in the Cardiosol-preserved organs (303 +/- 29.8 microU/ml) (+/- SEM) than in the glands preserved in UW solution (112 +/- 47.9 microU/ml). We conclude that Cardiosol allows prolonged whole organ pancreas preservation in the rat transplant model.

Adenosine↗
PubMed1990

Pancreas and islet-cell transplantation. Potential cure for diabetes.

In the past two decades, results of whole-organ pancreas transplantation have improved considerably. Patient survival rates of 95% to 100% and graft success rates of more than 70% at 1 year have been reported. After successful transplantation, exogenous insulin can be discontinued and the patient's quality of life improved. In the field of islet-cell transplantation, remarkable progress has been made in isolation techniques. However, the problem of rejection without serious sequelae remains. Immunoisolation of islet cells in microcapsules offers an exciting solution, but research is still in preliminary stages. Early results in large animal models are extremely encouraging.

Adult↗
PubMed1990

Rapid purification of islets using magnetic microspheres coated with anti-acinar cell monoclonal antibodies.

A simple, rapid method of islet purification is important in large-scale human islet isolation. We have previously identified monoclonal antibodies specific for acinar cells, but not islets, and described an immunologic method of purification by selective lysis of the acinar cells. An attractive alternative to lysis of the acinar cell is depletion by a magnetic immunomicrosphere technique. We report in this study a rapid, reproducible method of rat islet purification utilizing magnetic microspheres coated with acinar-cell-specific monoclonal antibodies. Pancreatic digestion with collagenase followed by depletion of acinar cells with the magnetic immunomicrospheres (MIMS) yields large numbers of intact islets. We compared the islets thus obtained with hand-picked (HP) islets (control) for yield, purity, in vitro insulin secretory capacities, and in vivo functional viability. The islet yield with the MIMS method (n = 35) was 72.7% that obtained with the HP method (n = 6) (378 +/- 8 vs. 519 +/- 31 islets per pancreas). The purity of the MIMS-isolated islets was 84 +/- 1.9%, ranging from 75-95%. Static glucose stimulation showed excellent function (2-3-fold increase of insulin release over basal levels) with no statistical difference in insulin secretion between MIMS and HP islets. Under microscopic examination, both groups revealed a well-preserved structure with healthy endocrine cells. When 1321 +/- 59 MIMS islets were transplanted into streptozotocin-induced diabetic rats (n = 10), normoglycemia (less than 200 mg/dl) was restored in all recipients following transplantation, and 100% of them remained normoglycemic on day 120 postgrafting. In summary, a rapid, consistent, and simple method of isolating viable, purified rat islets is described. The broad interspecies crossreactivity of the McAb suggests that this technique may be generally useful for islet purification in large mammalia, including man.

Animals↗