The Promise and Challenges of Islet Cell

Encapsulation
By Meghan Tighe

Abstract
Type 1 diabetes (T1D) is an autoimmune disease that results in destruction and permanent loss
of insulin-producing beta cells. Because insulin is crucial to the processing of glucose, people
with T1D are required to take insulin injections multiple times per day. Insulin treatment,
whether through multiple daily injections or pump therapy, allows those with T1D to continue
living without beta cells but is in no way a cure. Rather, it is a temporary solution, one that
extends life expectancy for years but leaves many issues in regard to quality of life.
Islet cell encapsulation has been investigated as a possible cure for T1D. The method
consists of a transplant of beta cells, sometimes along with other Islet cells, into a person with
T1D. This allows the person to once again produce and secrete insulin in response to glucose
concentration. The implanted cells are protected by a semipermeable membrane that allows
glucose, nutrients, and oxygen into the membrane, allows metabolic waste and insulin to leave
the membrane, but provides a sufficient barrier to protect the transplanted cells from the host
immune system.
As clinical trials of islet cell encapsulation continue, the remaining issues with this
treatment may be solved in a way that allows islet cell encapsulation and transplantation to be
the new standard of care for people with type 1 diabetes.

Introduction
A person with a healthy, functioning pancreas has a feedback loop that causes the body to
secrete insulin and glucose as needed to maintain a healthy blood glucose concentration.
Critical to this system are the islets of Langerhans: groups of cells located in the pancreas that

primarily consist of alpha cells, beta cells, and delta cells (Figure 1). Beta cells, which make up
about 70% of islet cells, secrete insulin in response to high blood glucose concentrations. This
function is necessary for the proper processing of carbohydrates (Baker).

Figure 1: Islets of Langerhans. The orange circle encloses one islet. Alpha cells (light blue) and beta
cells (dark blue) secrete glucagon (blue circles) and insulin (purple triangles) respectively in response to
glucose (green circle) concentration. Oxygen is supplied from blood vessels shown in red. Figure from
http://transplant.surgery.ucsf.edu/conditions--procedures/islet-transplant-for-type-1-diabetes.aspx.

Type 1 Diabetes
Type 1 diabetes (T1D) occurs when a person undergoes significant and eventually
complete loss of beta cell mass. This leaves them unable to produce insulin to regulate glucose
levels and leads to hyperglycemia. T1D has a genetic component but is initiated by an
environmental trigger (Baker). This trigger commences beta cell destruction through a variety
of mechanisms. B cells and T cells both contribute to this process, by producing autoantibodies
and by direct cell-mediated beta cell attacks respectively (Belle). Cytokines, including as
interleukin-1 beta and tumor necrosis factor alpha, concurrently cause a cyclical process of
beta cell destruction by causing beta cell apoptosis, inflammation, and beta cell proliferation at
different points in the process. Through these combined mechanisms, as well as others still
being studied, T1D leads to destruction of beta cells and the inability to secrete insulin (Cnop).
The current standard of care for people with T1D is insulin therapy, through either
multiple daily injections or insulin pump therapy. Insulin therapy serves as a survival

mechanism for people with T1D but is not a cure. Those on insulin therapy will be dependent
on insulin for the rest of their lives and also face a shortened life expectancy and lower quality
of life. In an ideal case, the use of insulin therapy will increase the life expectancy of an
individual to only ten years below average (Belle).
An alternative method of treatment is a full pancreas transplant. This method is less
common and is typically only used in patients with hard to control diabetes who are already
undergoing an organ transplant. The biggest drawback to pancreas transplants is the need for
immunosuppression (Belle).
Immunosuppression suppresses the patients immune system so that transplanted
tissue is not rejected. This treatment is unideal for many reasons. First and foremost, it leaves
the patient vulnerable to infection. Immunosuppressive drugs can also have problematic dayto-day side effects such as nausea and vomiting. Furthermore, some of these drugs can cause
detrimental effects if taken during pregnancy or while breastfeeding (Giorgi). Encapsulation of
transplanted tissue offers a more robust treatment in which patients no longer have to rely on
daily drugs and dont have to face increased susceptibility to infections.

Islet Cell Encapsulation

Islet cell encapsulation has been investigated as a possible cure for T1D. The method
consists of a transplant of beta cells, sometimes along with other Islet cells, into a person with
T1D. This allows the person to once again regulate their own blood sugar by producing and
secreting insulin in response to glucose concentration. Because this foreign tissue would
regularly be rejected through immune response, the cells need to be protected from the hosts
immune system. Approaches to this issue include suppression of the hosts immune system or
encapsulation of the cells before transplantation.
Encapsulation requires a semipermeable membrane that allows glucose, nutrients, and
oxygen into the membrane, allows metabolic waste and released insulin to leave the
membrane, but provides a sufficient barrier to protect the transplanted cells from the host
immune system (Figure 2). The size and shape of the membrane is different for different
encapsulation techniques, as will be discussed later in this paper.

Figure 2: Islet Cell Encapsulation. Basic requirements of beta cell encapsulation membrane include a
semipermeable membrane that allows nutrients to flow into the capsule, allows waste and insulin to
exist the capsule, but maintains a boundary between transplanted cells and host immune components.

The History and Current State of Clinical Trials

Experiments in islet transplantation began in 1994 (Curry). Animal trials of beta cell
encapsulation have produced successful results in rodents for years (Weir, Vegas). Human trials
so far have been less successful, due to a variety of challenges, introduced below (Scharp). A
variety of technologies and methods are being researched to overcome these challenges and
several of these projects are beginning or are already undergoing clinical trials.
Beta O2 Technologies BetaAir device is currently undergoing a second round clinical
study after completing a successful trial with one patient in 2012 (Beta O2). ViaCyte is
conducting a clinical trial, of their VC-01 encapsulation device, and is planning another clinical
trial of their second device, the PEC-Direct (ViaCyte). The Diabetes Research Institute is
currently seeking participants for the first clinical trial of their BioHub mini-organ
encapsulation device (Diabetes Research Institute). No devices have yet completed clinical
trials with sufficient results to warrant commercial product release.

Challenges of Encapsulation
Availability of cells
One major roadblock for beta cell encapsulation as a form of treatment is the lack of
availability of beta cells for transplantation. There are several possible sourcesallographic
transplants, xenographic transplants, and stem cellseach of which has different advantages
and disadvantages, outline in Table 1.
In xenographic transplants, cells are taken from nonhuman donors. Past work has
mainly utilized porcine cells. One advantage of porcine cells is that there is considerable
knowledge about the effect of porcine insulin in the human body (Weir, Gray). Although
porcine cells are easier to access than human cells, xenographic implants increase the
likelihood of rejection by the host (Orive). Additionally, the use of porcine and other nonhuman beta cells gives rise to ethical concerns. Abolitionists object to any use of animals in
testing or treatment for humans, even in life-saving scenarios. A larger group of more
moderate objectors believe that the ends can justify the means but changes need to be made
in the conditions under which these animals are raised (Singer). Although encapsulation with
porcine islets has produced successful preliminary results in clinical trials (LCT Global), most
current clinical trials seem to be moving away from using non-human cells.
Allographic transplants pose less of a challenge in preventing immune response but
have the substantial disadvantage of being difficult to obtain. Part of this is simply due to the
dearth of donors (Scharp, Baker, Orive). Furthermore, a single recipient typically requires
multiple donors. This is in part due to a low yield in the beta cell isolation process (Gray). In
addition to having a low yield, this process can also fail to eliminate dead and dying cells in the
pancreas (Weir).
Another possible source of cells for transplantation is stem cells. This method is based
on the theory that with exposure to certain signals, embryonic stem cells extracted from
blastocysts can be manipulated to differentiate into insulin-producing beta cells. However, the
implementation of stem cells as a source as not yet been executed in a way that yielded
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repeatable, long-term results (Meier). In 2014, ViaCyte began the first clinical trial of beta cell
encapsulation that used stem cell-derived beta cells. Engineers at ViaCyte engineered beta cell
precursors from embryonic stem cells and encapsulated them inside their VC-01 marcoencapsulation device. Results of their 2-year study are expected to be released in August 2017
and will hold strong implications for the future of embryonic stem cells as a source of
functioning beta cells for transplantation (ViaCyte).
It has also been suggested that adult stem cells could be made to differentiate into beta
cells. These stem cells could be extracted from the exocrine pancreatic parenchyma,
pancreatic ducts, islets, liver, spleen, or bone marrow. Recent research conducted in rodents
suggests that no new islets are formed through differentiation of stem or progenitor cells
during adult life. Research into adult stem cells as a source for beta cells is ongoing and more
studies are needed to determine viability of this concept (Meier, Dor).
Beta Cell Sources
Cell Type

Advantages

Disadvantages

Xenographic

Wide availability

Allographic

Fewer immune concerns

Immunologically challenging
Ethical concerns
Lack of donors

Stem Cell

Theoretical availability
Could be autograft transplants

Little research done so far

Table 1: Beta Cell Sources. Each potential source of beta cells for transplant, including xenographic
cells, allographic cells, and stem cells, has advantages and disadvantages.

Semipermeable Membrane
The transplanted cells have to be protected once implanted inside the host body.
Unprotected cells would not survive, not only due to the hosts beta cell attacking antibodies,
but also due to the hosts normal immune response to foreign tissue.
Immunosuppression is often used in organ transplants to avoid host rejection. While
effective, immunosuppression leaves the host vulnerable to malicious foreign invaders. For this
reason, it is preferable to create a tolerance to the foreign tissue rather than suppressing the
immune system (Orive, Baker). Unfortunately, creating this tolerance is not simple. As of 2014,
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only a single encapsulation technique had been approved for implantation without
immunosuppression of the host (Scharp).
To achieve tolerance of foreign material, it is necessary to create a membrane that
separates the implanted cells from the immune components of the recipient. The membrane
must be able to keep not only cells but also antibodies and complement from entering the
capsule. A variety of both synthetic and natural materials would be able to achieve this.
It is significantly more challenging to find a material that allows selective transport
across the membrane. For the cells to remain functional, they need to be able to receive
nutrients from outside of the capsule as well as to secrete metabolic waste. It is also necessary
that glucose and insulin are able to travel across the boundary so that the insulin produced can
have its intended effect (Orive, Weir, Scharp). Due to the similarity of size between insulin (~6
kDa) and potentially harmful cytokines (2-30 kDa), the selectivity of the membrane cannot be
based solely on size (Vaithilingam).

Materials
There are a variety of materials used to encapsulate transplanted cells. Each of these must be
able to allow the required diffusion, protect the transplanted cells, be compatible with the
hosts immune system, and form flexible, soft scaffolds for the cells. Investigated materials
include polyethylene glycol, polyvinyl alcohol, polyurethane, polyethersulfone, polypropylene,
sodium polystyrene sulfate, polyacrylate, agarose, chitosan, cellulose, collagen, xanthan, and
alginate (Orive). The most common material is alginate hydrogel (Weir). Alginate is the only
material that has been qualified as safe for human application (Orive). Although use of alginate
is common, there are no standardized formulations for the makeup of the material that
provide reproducible results when used in beta cell encapsulation (Weir).

Viability of Cells
Cell viability is a central concern in beta cell transplants. Several important factors affect cell
viability and will be discussed independently in detail. Although some studies show that

encapsulated cells can remain functional for years (Weir), there is a consistent high level of cell
death upon transplant, regardless of technique (Scharp). Several methods have been
implemented, with varying levels of success, to increase long term cell viability. The obstacles
to cell viability, as well as their possible solutions, are described below.

Oxygenation
One common obstacle for cell viability is hypoxia. To remain viable, the implanted cells need a
constant reliable oxygen source. If cells are allowed to clump, those in the center will lack the
necessary oxygen supply and die (Figure 3). It is necessary for the capsule to have sufficient
surface area to ensure oxygen supply to all cells (Weir). As discussed in a later section, the need
for oxygen supply has spawned research into different sizes and shapes of capsules. Many
studies are conducted to investigate methods of preventing hypoxia (Baker).

Figure 3: Hypoxia in Clumped Cells. Clumping of cells allows for only those on the exterior to receive
sufficient oxygenation. Interior cells will become hypoxic and die. Figure reprinted from Weir.

One possible mechanism for promoting oxygenation of beta cells is through utilization
of different materials. For example, Khattak et al. designed a study to test the ability of
synthetic oxygen carriers to increase oxygenation. The authors incorporated
perfluorooctylbromide (PFOB) into the alginate encapsulation device. This material was
selected due to its prior reported success and approval for use as an oxygen carrier in humans.
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This study chose to look at the encapsulation of Hep G2 cells but is still relevant to
encapsulation of other cells, including islets. Lactate and lactate dehydrogenase (LDH) levels
were considered indirect indicators of oxygen availability. Results indicated that incorporation
of PFOB into a culture of oxygen-deprived Hep G2 cells showed an increased level of metabolic
activity that was statistically significant (Khattak). This study shows just one type of material
that could be utilized to increase oxygenation.
Ludwig et al. designed a macro-encapsulation device that incorporated a unique
method of ensuring cell oxygenation. The design (Figure 4a) included a central oxygen module
that was supplied with oxygen from oxygen ports that went through an incision and connected
to an external manual pump that the patient could use daily to supply oxygen. The device was
implanted into a patient with T1D without use of immunosuppression. The patient sustained
insulin independence for a period of ten months, at which point the device was removed for
investigation. The analyzed islets (Figure 4b) showed present and normally distributed beta
cells and alpha cells, as indicated by staining for insulin (green) and glucagon (red). This trial
demonstrates the importance of oxygenation and the promise of beta
cell encapsulation once this issue is better addressed (Ludwig). A variation of this
device, now named the Beta Air, was approved for and began clinical trials and 2014. Results
from this trial has not yet been released (BetaO2).

Figure 4: Oxygen Supplied Macro-encapsulation Device. A) This macro-encapsulation device consists

of two islet modules, separated by a central oxygen module. Ports supply the central module with
oxygen through use of an external pump. B) Islets extracted after 10 months show appropriate
distribution of insulin-secreting beta cells (green) and glucagon-secreting alpha cells (red). Figure
adapted from Ludwig.

Matrices
Many studies transplant beta cells within some type of matrix complex to increase cell viability.
A common practice is the use of collagen type IV and laminin, which are both fibrous proteins
that exist in the extracellular matrix (ECM), as a matrix for cell encapsulation. Figure 5
demonstrates results of a basic study investigating beta cell viability when encapsulated in a
Collagen IV matrix or a Laminin matrix, as compared to viability with no incorporation of ECM;
cell viability is significantly higher when transplanted in the matrices. Further investigation
showed that cell viability is even higher in a matrix incorporating both Laminin and Collagen
(Weber).

Figure 5: Encapsulation of Beta Cells in Collagen IV and Laminin Matrices. Beta cell viability,
evaluated by insulin production, is significantly higher when cells are encapsulated in matrices
containing Collagen IV or Laminin. Figure adapted from Weber.

Many methods include variations of this makeup. For example, Davis et al. incorporated
silk fibroin proteins from the Bombyx Mori silkworm into the matrix. Silk was considered for
this application because it supports cell adhesion, proliferation, and differentiation. Results
suggest that silk fibroin proteins used in combination with collagen and laminin increase cell
viability (Davis).

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Co-encapsulation
With or without inclusion of a matrix complex, beta cells can be co-encapsulated with
other cells. One unanswered question about beta cell transplantation is whether it is necessary
to include other islet cells. Results do suggest that inclusion of islet cells such as alpha cells and
delta cells improves insulin secretion by beta cells (Meier).
Jourdan et al. conducted a study to investigate the hypothesis that insulin-like growth
factor 2 (IGF-II) increases insulin secretion by beta cells. The study was conducted by
measuring insulin secretion by three different groups: islets alone, islets co-encapsulated with
murine TM4 cells stably overexpressing the green fluorescent protein (GFP) gene, and islets
co-encapsulated with TM4 cells overexpressing the IGF-II gene. The GFP co-encapsulated
group served as a control to account for any effect of the TM4 cells that wasnt due to the IGFII. Results, shown in Figure 6, demonstrated significantly higher viability of beta cells over time
when co-encapsulated with IGF-II (Jourdan).

Figure 6: Viability of islets encapsulated with IGF-II expressing TM4 cells. Mice that were
transplanted with both islets and IGF-II expressing TM4 cells had significantly higher rates of
maintained normoglycemia over a 151-day period. Figure adapted from Jourdan.

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Location
Another question in beta cell transplantation is the best location for the transplant. The
location needs to have sufficient oxygen supply, due to the cells sensitivity to lack of oxygen
(Meier). Cells were originally transplanted into the intraperitoneal region (Gray). Islet cells have
since been transplanted into the liver, kidney, bone marrow, and subcutaneous tissue (Souza).
Transplantation into the intraperitoneal region has now been determined to be less ideal and
can require two to three times as many cells as a transplant into the kidney due to decreased
vascularization (Gray). Some locations, such as in the intestinal mucosa, have the benefits of
rich vascularization and an abundance of growth factors, but are technically challenging for a
surgeon to implant (Meier).
In current clinical settings, cells are typically transplanted into the liver via the portal
vein (Sakata), however, alternate locations are still being investigated. The Diabetes Research
Institute (DRI) is currently recruiting patients to participate in a clinical trial to investigate the
efficacy of a new transplant location: the omentum, a lining that covers the abdominal organs.
Although the DRI provides little explanation, they hypothesize that this transplant location will
increase long-term islet viability. This and other projects focus on new transplant locations as a
method of increasing success of islet encapsulation and transplantation (Diabetes Research
Institute).

Encapsulation Techniques
Cells can be encapsulated in various manners, as seen in Figure 7. Methods of encapsulation
determine where the implantation can take place. They also serve as a factor of cell viability.
Due to islets need for oxygen, the size of the encapsulation device is extremely important.

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Figure 7: Decreasing Change in Islet Size Based on Encapsulation Method. Encapsulation techniques
can add significant size to the islets. Figure reprinted from SoRelle.

Macro-encapsulation consists of the implantation of a device containing multiple islets.

The most common locations for transplant, such as the portal vein of the liver, are not suitable
for such large implants which can be up to several centimeters in length. For this reason,
macro-encapsulation devices are typically implanted subcutaneously (Weir). Macroencapsulation devices are advantageous in that they are easy to monitor and can be removed
if necessary (Curry).
Micro-encapsulation consists of implanting many beads which each contain a single
islet. This was the first method that showed effective and repeatable results (Gray). This gives
encapsulated cells better access to oxygen than they would have in macro-encapsulation
devices. However, the diameter of a micro-encapsulation membrane can still be more than five
times that of an islet cell alone. This has significant detrimental effects on the cells access to
oxygen, as discussed later in this paper (SoRelle).
Attempts to decrease the size of encapsulated islets resulted in the invention of
conformal coatings. These coatings, often made of polyethylene glycols (PEG) such as
diacrylate, increase islet diameter by approximately 50 m, resulting in a final diameter of only
about 200 m. At this size, islets are difficult to monitor or to remove if necessary (SoRelle,
Weir).

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PEGylation goes one step further in maintaining a minimal islet diameter. This method,
previously used to immunoisolate red blood cells, attaches long chains of PEG to the surface of
the islet. This allows the beta cells to maintain viability and function while staying masked from
the immune system. PEGylation offers the advantage of only microscopic additions to islet
diameter. However, investigation into robustness of the technique over time is limited and
should be further researched due to the dynamic nature of the islet surface and the importance
of long lasting immunoisolation (SoRelle).

Risk of Sensitization
Beta cell encapsulation comes with a set of risks for the recipient. One of these risks is
sensitization. Many people with T1D, especially those who have experienced high amounts of
hyperglycemia, need organ transplants at some point in their lives. In fact, about 30% of
people with T1D will experience kidney failure in their lifetime, for which kidney transplants
have been proven a better treatment option than dialysis (Diabetes, Kim). It is possible that a
recipient could become sensitized to foreign tissue, making it harder for them to find a suitable
donor if they later need an organ transplant (Scharp).
This means that a person who chooses to receive an islet cell transplant may be unable
to receive a successful kidney transplant in the future. Because the likelihood of people with
T1D who need organ transplants is so high, the risk of sensitization is a major issue.

Conclusion
As demonstrated by this paper, beta cell encapsulation and transplantation is one extremely
promising solution to the production of insulin in people with T1D. When implemented
successfully, beta cell encapsulation eliminates the need for immunosuppression with islet cell
transplantation. This allows people with T1D to remain insulin independent without becoming
vulnerable to other diseases and infections. There are many challenges that stand in the way of
this technology becoming a permanent solution, which have been outlined above. With

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continued funding and efforts, sufficient solutions may arise that allow beta cell encapsulation
to continue past the clinical trial stage within the next decade.

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