Artificial Pancreas and Islet Cell Culture, by Alan Mann

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==Overview==
==Overview==
An artificial pancreas is a system, whether living or non-living, that is mainly used to treat diabetes mellitus by releasing insulin into the bloodstream in response to changing blood glucose levels. The main goal in researching various types of artificial pancreases is to produce a “closed-loop” system, whereby various components of the system are able to detect changes in blood glucose levels, and to simultaneously release insulin in response to these changes.  
An artificial pancreas is a system, whether living or non-living, that is mainly used to treat diabetes mellitus by releasing insulin into the bloodstream in response to changing blood glucose levels. The main goal in researching various types of artificial pancreases is to produce a “closed-loop” system, whereby various components of the system are able to detect changes in blood glucose levels, and to simultaneously release insulin in response to these changes.  

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Contents

Overview

An artificial pancreas is a system, whether living or non-living, that is mainly used to treat diabetes mellitus by releasing insulin into the bloodstream in response to changing blood glucose levels. The main goal in researching various types of artificial pancreases is to produce a “closed-loop” system, whereby various components of the system are able to detect changes in blood glucose levels, and to simultaneously release insulin in response to these changes. Current methods of insulin administration such as insulin injections do not mimic natural insulin release by the pancreas within the body. A healthy pancreas continuously measures changes in blood glucose levels, and releases small amounts of insulin in response to these changes. Current insulin injection methods involve administration of large doses of insulin at a time, leading to imbalances between blood glucose and insulin levels. Thus, a successful continuous “closed-loop” insulin delivery system design will greatly improve current methods of diabetes treatment. Insulin pumps have been a topic of study since the 1970s, and new models are coming closer to achieving natural insulin release[8]. Likewise, islet cell culture therapies have shown some success in diabetes treatment, and remain the primary focus of future studies in diabetes treatment [12].

History

A general overview of the history of diabetes treatments leading up to modern areas of research includes the following:

  • 1921-Banting and Best refine insulin from canine pancreas extract, and successfully treat a child dying from diabetes [8].
  • 1935-Roger Hinsworth discovers the difference between type 1 and type 2 diabetes [8].
  • 1930s to 50s-new types of insulin improve treatments for various types of diabetes [8].
  • 1961-The single use syringe is invented, greatly reducing pain caused by injections and eliminating the need to sterilize a needle for injection [8].
  • 1969-The first portable glucose meter is created, enabling patients to test their own blood glucose levels [8].
  • 1970s-Research in glucose electrode technology begins [9].
  • 1979-The first insulin pump design is invented, delivering continuous insulin supply to the patient [8].
  • 1990-For the first time, nine patients are treated with human islet transplantation [10].
  • 1999-Medtronic MiniMed becomes the first Continuous Glucose Monitoring (CGM) system approved by FDA [9].
  • 2000s-Islet transplantations become more common, techniques more researched, insulin pumps become more advanced.

Continuous Glucose Monitoring (CGM) Systems

General

Continuous Glucose Monitoring (CGM) systems have been researched and developed since the 1970s [8], [9]. The vast majority of CGM systems involve the use of a few simple parts [9]. First, a glucose sensor detects changes in blood glucose levels within the body [9]. A transmitter then relays blood glucose information to a receiver [9]. The receiver displays this information on a screen, so that the patient can monitor his or her blood glucose levels continuously [9]. The receiver and screen are part of a device which also contains a cavity filled with insulin, and a tube that is inserted subcutaneously into the patient [15]. The CGM system can be set to a target blood glucose level, and will automatically release the required amount of insulin necessary to maintain the target level of blood glucose [1]. Most CGM systems record blood glucose levels every five minutes automatically [9]. This provides the patient with a better method of continuously monitoring blood glucose levels, since blood glucose monitoring by “finger pricking” is not a feasible method of checking blood glucose levels every five minutes. Many newer models of CGM systems are also equipped with an audible alarm, which sounds if blood glucose levels become too low or too high [1].

Functional Issues

The main functional problems involved with most CGM systems have to do with inaccurate detection of blood glucose levels by the glucose sensor. Blood glucose sensors tend, on average, to over-predict the blood glucose levels of the patient by about 10-16% when in the range of 70 to 180 mg/dL of blood glucose (the healthy “target” range is between 70 and 100 mg/dL) [1]. This presents a considerable risk of hypoglycemia, especially when sleeping or undergoing other long periods of fasting [1]. Additionally, glucose sensors often tend to “lag” when blood glucose levels undergo a rapid change, for example, during the couple of hours after eating a large meal [1], [2]. In this case, blood glucose levels will rise rapidly due to food consumption, and the sensor will under predict the actual blood glucose level of the patient [1], [2]. In order to maintain healthy blood glucose levels, several precautions can be made when using CGM systems. In order to avoid hypoglycemia, patients can adjust the target blood glucose range to a higher level before bed, or before long periods of fasting [1]. This will adjust for error in blood glucose levels recorded by the glucose sensor. Additionally, equipping a CGM with a supply of glucagon has been proposed [1]. Glucagon is a chemical which, when blood glucose levels begin to drop, leads to the depolymerization of glycogen in the liver and the subsequent release of glucose to the body [5]. Thus, it presents a rapid means of delivering glucose in the event that hypoglycemia should occur in the patient. Some studies have shown that to prevent rapid increase in blood glucose levels following a meal (due to the “lag” effect of the glucose sensor) patients can manually inject a small dose of insulin about 15 minutes prior to eating [1]. This will ensure that a higher amount of insulin is being administered to balance out the high amounts of glucose consumed during a mealtime.

Islet Cell Culture

Islet cells consist of aggregates of three main cell types (α-cells, β-cells, and δ-cells), which exist and function properly in a healthy human pancreas [16]. The release of glucagon by α-cells, combined with the release of insulin by β-cells, allows the pancreas to continuously monitor and stabilize blood glucose levels [16]. In an islet transplantation procedure, islet cells are taken from the pancreas of a patient or suitable donor, cultured in a lab, and subsequently transplanted back into the patient, usually to the liver [12], [13]. The transplantation is performed using a simple catheter, which is inserted into the portal vein of the liver [12], [13]. Islet cell aggregates travel into small capillaries throughout the liver, where they become “stuck” due to size limitations [13]. There, the cells act as they normally would in the pancreas, releasing insulin (and glucagon) in response to changing blood glucose levels [12], [13]. Since insulin secreted from the pancreas normally travels to the liver, the liver has been shown to be the most suitable location for islet cell transplantation [13].

Complications of Islet Cell Therapy

In a 2005 study involving 65 patients who underwent islet cell transplants, only about 10 percent of the patients were insulin independent after 5 years [12]. A 2006 study showed that after 6 months, over half of the 225 patients involved were insulin independent [12]. At the 2-year mark, however, that number dropped to one-third [12]. Several complications give rise to the above results. The biggest issue facing patients who have received islet cell transplants is an immune response [7], [12]. Research shows that in large animals such as dogs and humans, an immune response to the transplanted cells is the largest cause of loss of cell viability with time [7]. Over the course of a few months, patients may need to return to manual methods of insulin administration. In order to prevent an immune response, several methods have been tested, leading to further complications. Immunosuppressive drugs have been used to prevent an immune response, but have led to other dangerous health complications [7], [12]. Also encapsulation of islet cells in man-made (usually polymer) membranes has been proposed to prevent an immune response [7]. This method, while fairly successful at preventing an immune response, has in the past eventually led to decreased islet cell viability due to poor diffusion of oxygen and other nutrients to the center of the islet cell aggregates [7].

Future Research

The Hanuman Medical Foundation hopes to create an encapsulated islet cell therapy using a macroscopic islet cell “sheet” release insulin in response to changing blood glucose levels [3]. By using a thin sheet to reduce problems with diffusion, Hanuman hopes to provide an islet cell therapy that enables canines to remain insulin independent for longer than an average of 93 days [3]. Bernard, Lin, and Anseth (2012) have produced a microwell cell culture platform that enables β-cells to form 3D aggregates [14]. Upon further study, they have found that these β-cell aggregates provide more natural cell-cell contact, and that this enables a higher percentage of the cells to remain viable over time [14]. Further studies in this area may lead to sustained viability of transplanted islet cell cultures in diabetes patients. 

References

  1. [1] http://go.galegroup.com.silk.library.umass.edu/ps/retrieve.do?retrieveFormat=PDF_FROM_CALLISTO&inPS=true&prodId=AONE&userGroupName=mlin_w_umassamh&workId=PI-0CUH-2008-MAY00-IDSI-96.JPG%7CPI-0CUH-2008-MAY00-IDSI-97.JPG%7CPI-0CUH-2008-MAY00-IDSI-98.JPG%7CPI-0CUH-2008-MAY00-IDSI-99.JPG%7CPI-0CUH-2008-MAY00-IDSI-100.JPG%7CPI-0CUH-2008-MAY00-IDSI-101.JPG&docId=GALE%7CA179241288&callistoContentSet=PER&isAcrobatAvailable=false
  2. [2] http://www.sciencedirect.com.silk.library.umass.edu/science/article/pii/S0169409X0300190X
  3. [3] http://www.hanumanmedicalfoundation.org/blog/2012/04/02/designing-a-definitive-islet-sheet-study/
  4. [4] http://www.medicinenet.com/script/main/art.asp?articlekey=52386
  5. [5] http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/pancreas/glucagon.html
  6. [6] http://www.jdrf.org/files/General_Files/Research_ENews/Frontline%203-07.pdf
  7. [7] http://www.hanumanmedicalfoundation.org/blog/wp-content/uploads/2012/03/Wang-et-al.-2008-Successful-Allotransplantation-of-Encapsulated-Isl.pdf
  8. [8] http://www.diabeteshealth.com/read/2008/12/17/715/the-history-of-diabetes/
  9. [9] http://apps.elsevier.es/watermark/ctl_servlet?_f=10&pident_articulo=90003190&pident_usuario=0&pcontactid=&pident_revista=326&ty=76&accion=L&origen=elsevier&web=www.elsevier.es&lan=en&fichero=326v27n01a90003190pdf001.pdf
  10. [10] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972674/?tool=pmcentrez
  11. [11] http://www.diabetes.org/diabetes-basics/diabetes-statistics/
  12. [12] http://diabetes.niddk.nih.gov/dm/pubs/pancreaticislet/
  13. [13] http://www.youtube.com/watch?v=l8Y-xj6L1LM
  14. [14] http://online.liebertpub.com/doi/pdf/10.1089/ten.tec.2011.0504
  15. [15] http://www.diabetes.co.uk/insulin/Insulin-pumps.html
  16. [16] http://www.elp.manchester.ac.uk/pub_projects/2000/mnby7lc2/pancreas.htm
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