





































� 

Berkeley
Pharma Tech
Journal of Medicine

Correspondence:�
avabagherian@virginia.edu

Keywords:
Diabetes
Encapsulation
Type 1 diabetes 
Microencapsulation
Stem cells 

Submitted May 6, 2022
Accepted June 9, 2022
Published July 19, 2022

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
Type 1 diabetes (T1D) is one of the most common chronic autoimmune diseases 
characterized by islet autoimmunity. This is followed by immune destruction of the β cells 
as T cells attack and destroy insulin-secreting pancreatic β cells, leading to insulin 
deficiency. Currently, life-long insulin therapy is the primary treatment option for the 
condition with research being centered around islet transplantation to restore glycemic 
stability. However, this procedure is limited by risks and supply shortages, highlighting the 
need for a safer, more effective therapy for the approximately 9 million people across the 
world with type 1 diabetes. This literature review assesses stem cells and their potential as 
a vast β cell supply towards the treatment of type 1 diabetes. Based on current findings, 
stem cells may differentiate to become a self-renewing β cell line that may reverse type 1 
diabetes; however, further studies expanding on ncapsulation techniques, methods 
whereby living cells are entrapped in semi-permeable membranes for the purpose of disease 
treatment, are required. With this new horizon of possibilities, targeted efforts towards 
stem cell manipulation in expressing β cell phenotype can pave the way for a high 
efficiency treatment for type 1 diabetes.

Reversing Type 1 Diabetes: The 
Magnifying Potential of Stem Cell 
Encapsulation
�ïw�Ava Bagherian, Anisha Jain, Darshita Prathap and Vanloan Nguyen



Introduction
Type 1 diabetes typically has a sudden onset during childhood or early
adolescence, often diagnosed when the child visits the hospital for one of
the condition’s symptoms. These symptoms include polyuria, increased
thirst, blurred vision, and weight loss¹. If not diagnosed within the �rst few
weeks, diabetic ketoacidosis (DKA), a condition in which excess blood acids
are produced, may develop². This condition is often fatal if left untreated
and is marked by abdominal pain, confusion, and nausea. Alternatively,
hypoglycemia, a condition in which the patient’s blood glucose levels are
low, is caused by excess insulin, low levels of eating, or excessive gaps of time
between meals³. Hypoglycemia and diabetic ketoacidosis are often caused by
missing insulin shots, especially if T1D is still undiagnosed. T1D, diabetic
ketoacidosis, and hypoglycemia may all be diagnosed through a urinalysis or
blood test that reveals abnormally high levels of glucose and blood acids.

The onset of T1D is typically sudden, making early diagnosis and treatment
integral. Stage 1 displays no symptoms, even when a patient’s hemoglobin
A1C, a blood test for prediabetes and type 2 diabetes, is tested⁴. However,
antibodies have already begun to destroy insulin-producing cells. Left
unnoticed, stage 2 characterizes itself with increased β cell loss and hence
abnormal blood glucose levels as a result. Though symptoms may still not
appear, the antibodies’ attacks have, at this stage, led to pancreatic damage⁴.
It is at this point, stage 3, where symptoms begin due to the great loss of β
cells. Though the direct causes of these stages are still unknown, certain
patients appear pre-disposed to the later stages.⁴

While direct causes of T1D are still unknown, some risks have been
identi�ed. Environmental risks, such as cesarean section births or the time in
life when cows’ milk is introduced into a child’s diet, have been associated
with the development of type 1 diabetes⁵. A popular theory linking the
environment to T1D links early-life viral infections to the condition’s
development⁵. Genetics have also been proven to partially cause type 1
diabetes, as the risk of developing the condition ranges between 1%-70%
depending on one’s genetic proximity to a family member with type 1
diabetes⁵. Additionally, certain drugs and medications can damage β cells,
reducing the production of insulin and causing a condition very similar to

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type 1 diabetes⁵. In some particular cases, such as a rodenticide introduced
in America in 1976 by the name of Pyrinuron, the medication can induce
the destruction of pancreatic β cells, hence leading to type 1 diabetes⁶.
Pyrinuron was withdrawn from the American markets after just 3 years;
however, other drugs may still lead to pancreatic in�ammation. These risks
for and causes of T1D are in need of further research because, as of now,
there is no cure for type 1 diabetes.

Figure 1: Damaged cells are unable to create insulin.

Previous studies have shown that stem-cell therapy may be developed into
an e�cient form of cell therapy for Type 1 Diabetes⁷. The goal of this article
is to comprehensively review and outline the most recent data surrounding
the bene�ts, risks, and details of stem-cell therapy as it relates to Type 1
Diabetes treatments. Even though treatments have advanced and the quality
of life of T1D patients has improved, T1D prevails as a widespread issue.

Currently, the most prevalent treatments include insulin injections,
continuous glucose monitoring devices, utilization of glucose tablets as
needed, and a general healthy lifestyle¹. As widespread as these options are,

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they hold great drawbacks. Insulin injections are a daily maintenance where
patients inject insulin subcutaneously in the area between the skin and
muscle, typically a location with enough adipose. If injected deeper by
mistake, low blood glucose levels combined with increased pain typically
occurs. Furthermore, injection sites must be rotated to avoid lipodystrophy,
a condition where adipose causes indentations that interfere with insulin
absorption⁸. Continuous glucose monitors, in contrast, involve inserting a
minuscule sensor under the skin that measures interstitial glucose levels
every few minutes⁹. The data is sent to a monitor, which is sometimes a part
of the insulin pump, for the patient to examine when needed. While this
option minimizes technically di�cult self-administered shots, it is limited by
a high cost that makes the device inaccessible to a large portion of the Type 1
population. Healthy lifestyles and glucose tablets may be used in
combination with traditional blood pricks and glucose monitoring.
However, these are not cures, nor do they reverse the e�ects of T1D. Due to
the prevalence of this disease, more e�cient treatments and therapies are
demanded.

Figure 2: Current popular type 1 diabetes treatments.

Stem-cell transplantation is an encouraging procedure in both cost and
safety. Stem cells are marked for their capacity to di�erentiate into di�erent

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types of cells, creating a large supply of any of the 200+ types of human
cells¹⁰, including bone marrow cells, red blood cells, nerve cells, and most
importantly for our purposes, islet cells. Hematopoietic stem cells, the
primary adult stem cells used in medical settings, are found in bone marrow
and are utilized to form blood cells¹¹. This allows for stem cells to be used in
integral procedures like bone marrow transplants and holds promise for
stem cells to be developed into other cells for other procedures. These
unspecialized adult stem cells (AsCs) can develop into islet cells for islet cell
procedures¹². Our goal has been to examine this potential procedure that
may be the key to a cure of type 1 diabetes.

Pancreatic cell transplantation is able to stabilize blood glucose levels on its
own, however, there is a chronic, nationwide shortage of donors and
immunosuppression therapy¹³. Islet cell transplantation is an alternative that
is less invasive than pancreas transplantation and also proves to be e�ective
in reversing complications from T1D but has similar limitations to pancreas
transplantation, still su�ering a lack of donors and hindering
immunosuppression therapy. AsCs and embryonic stem cells (ESCs) can be
di�erentiated into pancreatic islet-like cells to produce insulin in response to
change in blood glucose levels¹⁴. This alternative is cost e�ective and involves
no donor shortages due to the self-producing cell line. However,
transplantation is a potential issue. Sourcing of human stem cells requires
exploring as new research heavily focuses on umbilical cord stem cells rather
than AsCs. Additionally, immunosuppression when stem cells are
implanted is still unclear, leading to the potential bene�ts of encapsulation
devices. Current strategies for this involve implanted cells shielded from the
immune system by a physical barrier. Encapsulated stem cell-derived islets
may shield β cells from the immune system, ensuring an almost limited
supply for islet cells in procedures to cure type 1 diabetes¹⁵. However,
encapsulation device strategies need to be improved in order to minimize
foreign body response, possibly by targeting di�erent sites. Moreover,
transplantation of stem cells through encapsulation in minimally invasive
areas is still being investigated. Nevertheless, this research emphasizes the
possible bene�ts within stem-cell therapy based T1D treatment and
highlights its need for future research.

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Current Cell Therapies
Current cell therapies in use hold signi�cant value as they can guide
scientists to potentially more e�cient and cost-e�ective alternatives. Stem
cell therapies today include regenerative medicine that causes repair
response. A major di�culty within these is that organ donors have to �t
restrictive criteria. The di�erent cell types, such as totipotent, pluripotent,
and embryonic stem cells, allow for a variety of treatments suited for
appropriate diseases¹⁶. It is of utmost importance to carefully select the type
of stem cells that are suitable for clinical application.

Speci�cally pertaining to type 1 diabetes, islet cell transplantations, where
islets are taken from the pancreas of an organ donor, contain beta cells that
produce insulin and have been used as a treatment for years now. Naturally,
with this treatment, di�culties such as limited supply of human islets and
poor immunosuppression arise¹⁷. Other potential treatments to reverse
T1D involve Mesenchymal stem cells (MSC), whose self-renewal potential
and ability to di�erentiation into functional cell types can cure diabetes¹⁸.
Potent strategies combatting these transplantation di�culties have been
explored: alternative transplantation sites, novel immune protective agents,
and encapsulation techniques. A clinical trial currently run by the
University of Alberta beginning 2021 evaluates pitfalls of islets but also
solutions to islet cell transplantation¹⁹. This highly bene�cial search for
higher e�ciency and safety as it pertains to current cell therapies is a major
factor as to why islet cells are a great therapeutic treatment method but also
why stem cells may be a better option.

Furthering the MSC treatment plan, one stem cell-based clinical trial for
Diabetes Mellitus is the intraportal allogeneic cadaveric islet transplantation.
Due to the lack of coverage for transplant costs along with the limitations of
cadaveric islets, alternatives have been sought, speci�cally regarding
Mesenchymal stem cells. As a source for newly generated beta cells, such
cells have been proven to be e�ective on type 2 diabetes. However, this is not
the case for type 1 diabetic patients, as Mesenchymal stem cells cannot
di�erentiate into beta cells as e�ectively in vitro. In vivo, this di�erentiation
does not occur at all. Instead, human embryonic stem cells are a plausible
treatment method that are being studied as surrogates in replace of cadaveric

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islets. Immune rejection however is a speci�c issue to this current cell
treatment that can be addressed. One potential research route, which will be
explained in more depth later on in this article, is the ability to couple hESC
derived organoids that produce insulin with microencapsulation
technologies. This optimizes the need for vascularization and can create a
more bene�cial route in reversing type 1 diabetes²⁰.

This research continues to advance in order to ensure safe therapy, as well as
develop e�ciency in utilizing adult stem cells, including bone marrow
transplants of hematopoietic stem cells. Speci�c future research targets
involve in vitro studies on the production of functional stem cell-derived
β-cells and how they respond to glucose. This will demonstrate how cells
respond to di�erent forms of beta cell stress. The protective mechanism
exhibited by suppressive immune cells in the pancreas shows promise for
future stem cell techniques and potential target sites. Similarly, human
pluripotent stem cells (induced pluripotent stem cells) serve as alternative
beta cell sources for transplantation when there are donor shortages for
other treatments. Another example of current/pursued research: beta cell
replacement through the transplantation of islets of Langerhan.

The �gure below details stem cell di�erentiation, the process by which stem
cells form more specialized functions through signaling mechanisms like
DNA methylation. The signaling mechanisms are transmitted through
nerve cells which generate electrical and chemical signals of action potentials
and neurotransmitters to send information. Blood cells are one type of
specialized cells that can be derived from stem cells, whose specialized
function include its self-renewal potential. In a study published in 2015, the
generation of sex cells through stem cell di�erentiation is explained,
providing new procedures for the e�cient generation of such cells from
embryonic stem cells, a speci�c stem cell discussed later. In the study, mouse
embryonic stem cells are signaled to di�erentiate into Epiblast-like cells and
�nally to PGC like cells, or primordial germ cells, a precursor to all germline
cells. The versatility of stem cells in di�erentiating into many key specialized
cells make them optimal for transplantation as it pertains to diabetes, as the
self-renewal potential and personalization of the treatment can prove to be
more e�ective and bene�cial²¹.

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Figure 3: Stem cell differentiation.

Limited donors comprise a portion of the di�culties with stem cell
treatments, but economic cost also plays a large role. For example, even costs
to create beta cells from stem cells are similar to the cadaveric islet method.
Both mechanisms, though useful and still developing, require more money,
and still immunosuppression issues and autoimmune rejection remain a
major factor in their ine�ciencies. So far, only a handful of trials have used
human embryonic stem cells in order to regenerate beta cells. While current
cell therapies include wearable insulin delivery devices made possible by
modern therapy’s increasing normoglycemic ranges—a signi�cant
improvement over regular insulin pumps—these are not stem cell therapies
and are no closer to reversing the e�ects of T1D. Rather, the ability to use
stem cells to enhance treatment by coupling it with other alternatives like
macro or micro encapsulation can prove to be much more bene�cial in the
long run.

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Combined Stem Cell Alternatives
Current stem cell therapies have been combined with other studied 
therapies and/or biomaterials to explore the ability to heal the e�ects 
associated with T1D or provide reversal treatment altogether. One 
combined stem cell therapy that has been explored to heal diabetic wounds 
is through treatment with human umbilical cord-derived mesenchymal stem 
cell-derived exosomes (hUCMSC-exos) and Pluronic F-127 (PF-127), which 
is a medicating hydrogel. PF-127’s unique thermal properties and porous 
structure allow for the release of therapeutic proteins, hypothesizing that 
PF-127 can continuously release hUCMSC-exos directly onto T1D-a�ected 
tissues, thus attracting �broblasts and endothelial cells to initiate wound 
repair22. This treatment was explored through topical application as this 
delivery was easy, convenient, and non-invasive, with high-e�ciency and low 
toxicity.

The treatment was tested by applying the exosome-hydrogel combination
on diabetic rat models, and the researchers observed angiogenesis, cell
proliferation, and granulation tissue formation to understand the
capabilities of this wound repair mechanism. The diabetic rats were tested in
three di�erent groups; one group was treated with hUCSMSC-exos only,
one with PF-127 hydrogel only, and the last with the combination
treatment of hUCMSC-exos/PF-127. It was found that after 7 days the
wound area was signi�cantly smaller in the combination groups versus the
others, and by day 14 the wounds were completely healed for this group²².
Combination treatment with hUCMSC-exos and PF-127 hydrogel allows
for the enhanced survival of exosomes and for a controlled release on wound
tissue over time which shortens the wound healing time. This study is a
notable example of how combined therapies can result in enhanced
treatment and accelerate healing time.

Further alternatives have been explored using insulin producing cell
therapies based on stem cells and combined transplantation with
Mesenchymal stem cells. Studies have shown that though MSCs prove to be
ideal cellular sources due to properties relating to tissue repair and
immunomodulatory capacities, further clinical trials have expanded on the
idea that its properties are not as e�ective as expected. Hence, a study

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combining MSCs and human Type 2 Diabetes islets ex vivo and in vivo was
performed exploring reverse beta cell dedi�erentiation5. The combination
of MSCs and islets presents a tempting alternative treatment, particularly as
adult MSCs su�er fewer ethical issues pertaining to self-renewal and
di�erentiation capabilities. Although this alternative has been explored with
Type 2 Diabetes islets rather than Type 1, it o�ers a novel strategy to reverse
dysfunctionality of beta cells, which is crucial given that they secrete insulin.

Coupling embryonic stem cell therapy with macro- and
micro-encapsulation devices has the potential to balance the necessity of
immune protection. This may serve as an innovative strategy to reverse T1D
and in the future may be used to overcome the issue of hosts’ immune
responses, improve immunoengineering strategies and encapsulation
technologies. A study involved the transplantation of human embryonic
stem cell-derived pancreatic progenitors in macroencapsulation devices into
diabetic mice. It aimed to create an improved di�erentiation protocol to
prevent forming excess tissue in places that weren't targeted, mainly the
mesoderm. This method explored how variations of environments could
in�uence in vivo pancreatic progenitor development. Such cells
di�erentiated into pancreatic endocrine tissue in macroencapsulation
devices, resulting in a reversal of diabetes within 3 months in the mice²³.
This process proved to be successful in generating grafts, necessary to fuel
islet cells, in greater than 80% of the endocrine cells. Furthermore, 99% of
tested mice did not show signs of formed non-endodermal cell populations,
providing evidence that an e�cient di�erentiation of human embryonic
stem cell-derived pancreatic endocrine cells has potential to couple with a
macroencapsulation device, even without direct contact with host
environment, ultimately making it capable of reversing diabetes e�ectively.

The �gure below illustrates the transplantation possibilities of functional
and isolated islet cells in maturation. In a study on the recovery of beta cell
de�ciency in type 1 diabetes, it was found that the beta cells regeneration is
due to endogenous regeneration or exogenous supplementation. This
means that transplantations of certain islets or grafting new beta cells from
in vitro cell engineering is a potential alternative through transplantation of
islets. Mice models have been used through transgenic expression to study

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inducible and reversible beta cell destruction. Ultimately, studies on
immunological mechanisms related to T1D and novel treatment strategies
such as grafting beta cells in vitro can prove signi�cant in �nding potential
type 1 diabetic drug targets for future clinical trials²⁴.

Figure 4: Islet cell transplantation.

Encapsulation Techniques

Figure 5: Cell encapsulation.

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I. Macroencapsulation
Macroencapsulation devices can assimilate islets into semi-permeable
membranes that elude typical immune responses while simultaneously
allowing for transplanted cells to transport insulin. Type 1 diabetes occurs
due to an autoimmune response which attacks insulin producing beta cells,
yet the complications of immune rejection of islet-like stem cells can be
prevented with macroencapsulation devices. Immunoprotection is achieved
by the selectively permeable membrane that impedes the movement of
immune cells and immunoglobulins into the device, while allowing the free
di�usion of oxygen, nutrients, insulin, and glucose to and from the
encapsulated cells. Stem cells are contained within a compartment of the
device which allows for selective exchange of nutrients and obstructs
antibodies from entering²⁵.

When considering macroencapsulation as a potential therapeutic for
reversing T1D, it is also crucial to consider implantation sites and shape
optimization to maximize the volume of the device within a space. A recent
study tested the posterior rectus sheath plane (PRSP) as a potential implant
site to host the macroencapsulation device. This plane is in between the
muscle belly and the fascia of the rectus abdominis muscle and this site is
being explored as implantation and retrieval can be performed without
invading the peritoneal space. PRSP has a large blood supply, allowing for
greater di�usion of nutrients, and the encapsulated cells therefore receive
adequate amounts of oxygen. In order to maximize the space in the PRSP,
the best shape for a macroencapsulation device here is presented to be a
polygonal-shaped device. These polygonal shapes are ideal as they deliver
signi�cantly more cells as compared to device shapes such as circles or
rectangles. Although a polygon-shaped device presents the most ideal
solution, the sharp angles pose challenges with manufacturing and patient
comfort. The polygonal shaped devices have favorable interactions with the
surrounding environment, and the implantation within diabetic pigs has
shown to be a minimally invasive procedure, but the long-term performance
of these devices remains untested²⁶.

Aside from optimizing the site-speci�c sites, a prominent problem with
macroencapsulation is being able to supply the encapsulated cells with

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enough oxygen. In a clinical trial published in 2018 studying the
encapsulation sites for optimal delivery of insulin, the βAir device was
developed to overcome this obstacle²⁷. The device contained allogeneic
human pancreatic islets and was implanted into 4 diabetic patients. Two key
sites that ensure easy access to minimal surgical intervention are the
pre-peritoneal cavity and under the skin. The signi�cance of these sites and
the overall use of the βAir device is to ensure retrievability and
immunoprotection. The results of the trial provided evidence that such a
device that utilized macroencapsulation was indeed safe and capable of
preventing rejection of implanted cells. However, metabolic control was
impacted with the transplanted cells' limited function. Potential claims for
the ine�ciency of the transplanted cells include hypoxia and hyperoxia
which could contribute to a lesser device volume, which is undesirable when
needing to deliver insulin and nutrients at a productive rate.

Macroencapsulation devices must support viability of the transplanted cell
at all stages through the maturation process. These devices are bene�cial as
they allow for immunoprotection of transplantation islet-like stem cells and
can also be retrieved with ease in any circumstance. One limitation present
with macroencapsulation devices is accessing a space for implantation. The
mechanics of the device are acted upon by di�erent external forces
depending on where implantation occurs, which can in turn limit the
functionality and lifetime of the device. Although recent studies have begun
exploring new sites and have been able to successfully implant islet-like stem
cells in microencapsulated devices in a minimally invasive fashion- the PRSP
is a great example of this type of site. Another major limitation is that islet
cell survival heavily depends on the supply of oxygen; this is a�ected by the
devices membrane permeability of oxygen, the rate of oxygen consumption
of the encapsulated islet cells, and other factors as well²⁸. One strategy that
has been considered to overcome any oxygen de�ciency that SC-islet cells
may encounter is oxygen delivery to encapsulated cells through oxygen
generating materials. In situ oxygen supplementation with the use of an
oxysite disk being placed within the center of the macroencapsulation device
has been shown to provide adequate oxygen supplementation and improve
the survival of cells²⁹.

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Unlike macroencapsulated devices, microencapsulated devices avert vessel
ingrowth, limiting the supply of nutrients to solely di�use through the
selectively permeable membrane. This may also result in a hypoxic
environment and therefore requires the need for oxygen delivering
technology within encapsulation devices.

II. Microencapsulation
Microencapsulation involves small islet cell mass which favors di�usion of
humoral factors and molecules from inside of capsules to the outer
environment. The devices are made of thin polymer �lms which tightly
adhere to individual islet or cell clusters. They occupy a very limited graft
volume and could be eligible for alternative graft sites. Issues may still arise
from e�ciency of immune barrier competence, the site of implant, and
dependence on the �nal microcapsules size. While conformal microcapsules
�t a wide array of potential graft sites due to their small size, the issue of
their long-term endurance arises. Furthermore, microencapsulation requires
an adequate oxygen and nutrient supply despite the decreased level of
invasiveness regarding the site of the microencapsulation transplantation.

In a research paper focused on microencapsulation devices, researchers
conducted a clinical trial to understand how an acquired immune tolerance
in patients with type 1 diabetes could prevent an autoimmune attack of
pancreatic islet beta-cells. Researchers studied G3C hybridoma triggering
the glucocorticoid-induced tumor necrosis factor receptor-related
costimulatory receptor (Gitr) to determine if this would promote expansion
of Tregs¹⁶. The G3C monoclonal antibodies were enveloped in
microcapsules which were engineered to allow selective �ow of
immunoglobulin M. In the end, researchers observed that long-term Gitr
triggering did induce Treg expansion and prevent diabetes from
development in NOD mice- this clinical trial shows promise that
microencapsulation can be a possible treatment for autoimmune diseases.

A study conducted in 2019 observed co-microencapsulation of human
umbilical cord-derived mesenchymal stem cells (hUCMS) and pancreatic
islet-derived insulin producing cells (hIDC), very similarly to what this
review proposes as a solution to reversing type 1 diabetes. NOD mice were

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grafted with microencapsulated hUCMS and hIDC and observed for 180
days. By the end, general health of these mice improved with signs of
increase in body weight and the cell co-aggregates were still intact and viable,
which proves that there was a su�cient exchange of nutrients³⁰. The
microcapsules were easily retrieved, which dismisses one of the main
limitations of microencapsulation techniques. Once retrieved, there were no
signs of pericapsular �brotic overgrowth, and insulin and glucagon were still
expressed. This study has shown that co-microencapsulation of
hUCMS/hIDC is successful and can o�er a new route of cell therapy of
type 1 diabetes. Considering the co-microencapsulation was successful
through this study, it is likely that microencapsulation of only human
mesenchymal stem cells (hUCMS) would also provide promising results for
reversing type 1 diabetes.

Microencapsulation is a viable method of encapsulating cells as it eliminates
the need for immunosuppressant medications by shielding cells from an
attack through the host’s immune system. The three-dimensional
microcapsule has a semipermeable membrane to allow for the exchange of
nutrients and waste, creating an optimal environment for stem cells to
survive. One major limitation of microcapsule transplantations is
pericapsular �brotic overgrowth due to a foreign body response, yet
research has shown that the use of a chemically modi�ed alginate derivative
can be e�ective in the prevention of overgrowth as it works to limit
movement and clumping. The study conducted with
co-microencapsulation mentioned earlier also proved that
microencapsulation techniques are viable and can be retrieved without
overgrowth occurring. Although pericapsular �brotic overgrowth is a major
limitation for the long-term e�ectiveness of microencapsulation, few
solutions have been found to overcome this obstacle.

III. Encapsulation Sites
Diabetic treatment using encapsulated islet cells has continued to grow with
new devices such as the aforementioned macroencapsulation and
microencapsulation. The importance of �nding a clear and e�ective site is to
allow for the e�cient glucose level regulations in an automated, continuous
manner. Several studies have sought an appropriate site for transplantation

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that limits the foreign body immune system response transplantation. For
example, the intravascular macroencapsules are particularly integral in
achieving a connection between solute transport and di�usion of
nutrients³¹. Some appropriate sites may include those in the vascular system
and may include shunts as well as di�usion chambers.

Finding an e�cient site limits any detrimental impact of foreign body
immune response. Such responses are a product of microencapsulation and
macroencapsulation sites, and their severity can include in�ammatory
responses and hypoxia. Hence, many factors play a role in determining
adequate sites such as material aspects on porosity, roughness, size of
implant, and surface charge. Current sites that are explored, however, are
generally limited in their space in renal capsules conventional sites, and the
respective volume of such sites is necessary in order to create a long-term
treatment of such encapsulation devices rather than a temporary solution.

Microencapsulation sites are ideal as they have increased ease of access for
implantation, retrieval, and imaging. Furthermore, there is a su�cient blood
and oxygen supply. The encapsulation site is still limited as the only site that
has been explored so far is the peritoneal cavity for implantation. Oher
implantation sites that are being explored include epididymal fat pad,
skeletal muscle, and subcutaneous tissue. However, transplantation in these
alternate sites remains an obstacle.

Macroencapsulation sites are large transplant masses within a single,
well-de�ned 3D device, allowing for device retrieval in case of adverse
reaction or failure. Most are implanted within the peritoneal cavity and
subcutaneous space. While the peritoneal cavity site of microencapsulation
allows for intrinsic high vascularity and oxygen tension, graft implantation
and monitoring generally requires invasive procedures. Subcutaneous space
transplantation is less invasive and also provides adequate oxygen which
facilitates cell survival.

A site for both macroencapsulated and microencapsulated islet-like stem
cells must be in close contact with the bloodstream for a su�cient supply
for nutrients, yet the liver and spleen (which typically host nonencapsulated

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islets successfully) are unable to tolerate the large volumes that are associated
with encapsulation techniques³². Due to less invasive procedures, most
transplantations of encapsulated cells are intraperitoneal, yet this site is not
practical as in�ammation and immune responses are associated with
intraperitoneal sites. Apart from intraperitoneal sites, kidney subcapsular,
subcutaneous, and under the skin spaces have also been tested and have
shown improved biocompatibility of encapsulated islets and a reduced
macrophage recruitment. These sites are being further tested for
encapsulation of islet cells to improve survival, engraftment, and function.

Figure 6: Encapsulation devices sites: supply of nutrients and oxygen.

Current issues involving sites that are more newly explored include death of
cells by hypoxia, a condition of low oxygen levels in cells. Impaired cell
growth and response due to hypoxia results in instability and lack of
function through other side e�ects like hyperglycemia and elevated levels of
fatty acid³³. Other detrimental e�ects that must still be researched include
the overgrowth of capsules in the macroencapsulation and
microencapsulation devices, since they may inhibit the e�cient transport of
nutrients to islets, further causing hypoxia as well as necrosis, the death of
body tissue due to too little blood �ow. This may cause delayed

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vascularization, or the improvement of nutrient supply, and ultimately lead
to the implanted cell destruction and graft failure, which is characterized by
the complications of allogeneic HSCT or the loss of donor cells.

Table 1: Macroencapsulation vs. Microencapsulation

Macroencapsulation Microencapsulation

De�nition System where 10^3- 10^6
islets are enclosed in a device
that contains a
semipermeable barrier.

In the context of T1D, acts
as a bioarti�cial pancreas,
immunoprotection
encapsulated beta cells

Made of thin polymer
�lms which tightly adhere
to individual islet or cell
clusters.

Bioengineering technique
capable of creating an
immune-privileged site

Bene�ts Allows the free di�usion of
oxygen, nutrients, insulin,
and glucose to and from the
encapsulated cells.

Evades the immune
response while
simultaneously allowing
delivery of insulin from
transplanted cells

Occupies a very limited
graft volume and could be
eligible for alternative graft
sites

Encapsulation
Sites

Most implanted within the
peritoneal cavity and
subcutaneous pace →
hypoxic condition & often
less vascularized
In order to provide
optimum nutrient
distribution, density of the
device should be 5-10% of
volume

The only site that has been
explored so far is the
peritoneal cavity for
implantation. Many other
sites are being researched
and will soon be explored.

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Limiting
factors

Contains a limited,
cell-loading capacity due to
reliance on di�usion. Slow
glucose stimulated insulin
secretion → scaling devices
for human application is
di�cult

E�ciency of immune
barrier competence, the
site of implant, and the
dual dependence on the
�nal microcapsules size.

Microencapsulated devices
prevent ingrowth of vessel
which limits the nutrient
supply to only di�usion
through the
semipermeable membrane

Discussion

Table 2: Implications

Practical Implications Theoretical Implications

Informs T1D patients/researchers of an
alternative to pancreatic
transplantation, which can be
inaccessible due to high costs and door
shortages

Beta cell transplantation has been
regarded as a plausible and e�cient
method of reversing type 1
diabetes.

No longer limited to ine�ective
transport of large/substantial
amounts of oxygen as well as
nutrients

Involves reversal potential of
Mesenchymal stem cells due to their
ability to di�erentiate into functional
cell types

Can o�er a proper control of
encapsulation devices on reversal of
diabetes to prevent foreign body
response

Proposals have the ability to
challenge current medical barriers
on �nding ideal transplantation
sites

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Poor immunosuppression increases the
need for more e�cient strategies, such
as exploring alternative transplantation
sites and various encapsulation
techniques.

Accessibility may be boosted,
breaking down �nancial barriers in
the journey to �nd the ideal
transplantation sites.

Selective sites can enhance the
compatibility of the devices as it
pertains to transplantation and
regulating the body responses, and
immune barriers can be
strengthened

Encapsulation o�ers optimal sites that
help implantation of islet cells.

Self renewing cells in the future can
provide a stable source of insulin whilst
also solving donor shortages

For future studies, there are
immune protective agents that can
better stabilize body responses and
provide for more e�cient,
alternative transplantation sites for
islet cells.

Both macro/microencapsulation
provide potential methods to prevent
detrimental foreign body response.

Studies and current proposals lead this
research towards reversing T1D in a
forward, productive direction.

Improving characteristics of
transport for nutrients and oxygen
through the encapsulation devices
and coupling it with other current
treatments can be an advanced
approach to reversing diabetes

As research on macro and micro encapsulation continues to develop,
potential pitfalls have been examined in order to further the e�ciency of
such processes. In a clinical trial held by PhD James Shapiro, such pitfalls of
islet transplantation speci�c to the foreign body response were addressed.
The trial induces the growth of new blood vessels and utilizes this foreign
body response to its advantage by modifying the target site. The participant
must have reduced awareness of hypoglycemia or metabolic instability and
be between 18-68 years old. Through an angiocatheter tube, a site is made
into a viable location, and islet transplantation will occur in the device-less
sentinel space and the transplant site is removed from the pocket. This is
one of the �rst human studies, and recipients of the islet transplants were

Berkeley Pharma Tech Journal of Medicine | 100



monitored. The outcome measures are to assess implant tolerability or the
rate of in�ammation at the site, as well as adverse e�ects on the participants
to assess the e�ectiveness of this harnessed foreign body response

Another ongoing trial from the City of Hope Medical Center aims to assess
a safer method of islet transplantation for normal control of blood sugar
without needing insulin shots. New onset diabetes is common due to an
organ transplant because of certain medications. The treatment is set to
transplant human allogeneic islet cells with varying dosage based on patients
weight. T1D patients between 18-60 years will receive immunosuppression
medication during treatment. The primary outcome measures of this study
are to reduce Hemoglobin A1c by at least 1 point, as well as eliminate
hypoglycemic events after the 1st islet transplant.

As detailed before, Mesenchymal Stromal Cells have ample potential to cure
diabetes with its ability to di�erentiate into di�erent cell types and for its
self-renewal abilities. A clinical trial, Cellular Therapy for Type 1 Diabetes
Using Mesenchymal Stem Cells, through the medical University of South
Carolina is meant to determine the e�cacy of metabolically active MSCs in
order to treat the new onset of type 1 diabetes as well as derive its
mechanism of protection. Currently ongoing, this research uses 50
participants that will receive treatment. Group A will receive a single MSC
infusion, and group B will receive a single infusion of placebo. The primary
outcome measure is a 12 month change in C-peptide area under the curve
and change in cell beta function. Since MSCs are e�ective and suppress
autoimmunity, the study aims to see MSC’s e�ect on insulin secretion rate,
change in islet autoantibodies, change in beta cell death measurements,
change in T-cell response, etc³⁴.

Finally, with the introduction of a coupling method between islet
transplantation and encapsulation devices, studies detailing the islet cell
transplantation process prove to be useful in assessing complications that
may arise. In an ongoing clinical trial on Improving Islet Transplantation
Outcomes With Gastrin, sponsored by the City of Hope Medical Center,
the e�ectiveness of Gastrin treatment with islet transplantation was
evaluated. Due to the limited supply of donor islets, the study seeks to test if

Berkeley Pharma Tech Journal of Medicine | 101



gastrin, which is a natural gut hormone present in the pancreas in the
embryo and a helper of the formation of the pancreas, can be injected to
make fewer number of transplanted islets work in a similarly e�cient
manner. For this study, participants with frequent hypoglycemic episodes
receive treatment with an islet transplant. For the next 30 days, they will be
injected with gastrin and continue the process, as well as take anti-rejection
medication, which is crucial because foreign body response as talked about
before can hinder the e�ects of the study.

Conclusion
Type 1 diabetes may be one of the most heavily researched autoimmune
diseases; however, the current research into the application and potential of
stem cells in pancreatic islet cell transplantation is nominal. The popular,
modern-day solutions of relying on CGMs, strict lifestyle routines, and
daily insulin injections are time consuming and outdated in comparison to
the potential of highly e�ective cell research. Stem cells can di�erentiate to
behave just like pancreatic islets and beta cells and can therefore produce
insulin, and this would eliminate the need for daily insulin injections. In
fact, stem cell implantation has proven to be one of the leading pathways in
transplantation, with current therapies including Mesenchymal stem cells,
human pluripotent cells, and even embryonic stem cells. However,
implantation can prove to have more obstacles than desirable such as cost,
limited donors, immunosuppression, and further unwanted foreign body
immune responses that may lead to death of the transplanted cells.

Implantation of stem cells alone is risky as the chances of a host immune
response is very likely, encapsulation techniques present a solution.
Encapsulation methods protect the encapsulated cells from an immune
response by the host, which would allow for continuous exchange of
nutrients and insulin and increase the life expectancy of these transplanted
cells as well. Clinical trials in humans have yet to be conducted to explore
encapsulation methods, but this solution has proven to be viable in NOD
mice and has the ability to provide reversal treatment for T1D. Details
surrounding the most e�cient encapsulation techniques and encapsulation
sites are unclear, but it is found that macroencapsulation and
microencapsulation provide viable solutions despite their many limitations.

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To further stem cell research, a coupling of such macroencapsulation and
microencapsulation devices may prove to be bene�cial in the long run when
facing technical issues by one device. A strategic employment of combined
alternatives such as the devices to embryonic stem cell therapy can be a step
towards reducing foreign body immune response as well as o�ering
immunoprotective strategies and increasing healthy cell proliferation and
nutrient exchange. The clinical trials mentioned before are currently in
progress to test out such theories and identify the collective bene�t of using
such strategies to reverse diabetes through noninvasive treatment.

According to the current state of research surrounding stem cell therapy, the
applicability of real-world stem-cell based islet transplantation is ambiguous.
Once further development in research is made, a conclusion based on the
biological, economical, and hazard-based results can be established. The
implications of the practical progress involving developing strategies for
better immunosuppression techniques and alternatives to current cell
transplantation methods set the foundation for diabetic reversal. Similarly,
theoretical implications including greater accessibility and alternative
transplantation sites provide a reliable pathway into the future of not just
diabetic reversal but for numerous autoimmune diseases. Once that future
research is advanced, stem-cell encapsulation may just be the key to clinical
cell therapeutics in the e�cient and safe reversal of type 1 diabetes.

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