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Current Diabetes Reports (2018) 18: 50

https://doi.org/10.1007/s11892-018-1028-y

IMMUNOLOGY, TRANSPLANTATION, AND REGENERATIVE MEDICINE (L PIEMONTI AND V SORDI, SECTION EDITORS)

Transplantation of Macroencapsulated Insulin-Producing Cells


Albert J. Hwa 1 & Gordon C. Weir 1

Published online: 16 June 2018


# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review There is considerable interest in using macroencapsulation devices as a delivery strategy for transplanting
insulin-producing cells. This review aims to summarize recent advances, to highlight remaining challenges, and to provide
recommendations for the field.
Recent Findings A variety of new device designs have been reported to improve biocompatibility and to provide protection for
islet/beta cells from immune destruction while allowing continuous secretion of insulin. Some of these new approaches are in
clinical trials, but more research is needed to determine how sufficient beta-cell mass can be transplanted in a clinically applicable
device size, and that insulin is secreted with kinetics that will safely provide adequate controls of glucose levels.
Summary Macroencapsulation is a potential solution to transplant beta cells without immunosuppression in diabetes patients, but
new strategies must be developed to show that this approach is feasible.

Keywords Macroencapsulation . Beta-cell replacement . Islet encapsulation . Oxygenation . Insulin kinetics . Type 1 diabetes

Introduction transplantation using cadaveric islets, as has been performed


in over 1000 patients worldwide [1]. These transplants usually
The hyperglycemia of diabetes results from insufficient insu- result in euglycemia, but even partial function will typically
lin production from the beta cells in pancreatic islets. In type 1 reduce the risk of severe hypoglycemic events, the major in-
diabetes (T1D), most pancreatic beta cells are destroyed by dication for which this procedure has been approved [2].
autoimmunity. In type 2 diabetes (T2D), there is a reduction in There is also evidence that control of glucose levels will limit
beta-cell number and those that remain have dysfunctional the progression of diabetic complications [3, 4]. However,
insulin secretion. In T2D, glucose levels can be controlled very few people can benefit from these transplants. The main
by drugs that can enhance insulin action on target tissues or limitations are (1) the availability of sufficient numbers of islet
stimulate insulin secretion, but it is often necessary to resort to cells for transplantation and (2) the difficulty of safely control-
insulin administration, since functional beta-cell mass is un- ling transplant rejection and autoimmunity.
able to secrete enough insulin to keep up with the metabolic While major strides have been made to address the first
demand. A more intuitive treatment for both diseases is to limitation, which include the use of pluripotent stem cells to
restore the functional beta-cell mass, which can be accom- produce insulin-producing cells [5–8] and the demonstration of
plished by transplantation of beta cells or islets. This has been effective pig islet transplantation in animal models [9], the sec-
demonstrated by whole organ pancreas transplants and by islet ond limitation is the requirement for immune suppression with
its attendant dangers. The use of encapsulation as a delivery
strategy could remove this limitation and thus greatly expand
This article is part of the Topical Collection on Immunology, the number of people who could benefit. Encapsulation tech-
Transplantation, and Regenerative Medicine
nology provides a physical barrier that prevents host immune
cells from entry, thus allowing the encapsulated cells to survive
* Albert J. Hwa
albert.hwa@joslin.harvard.edu and function without the need for immune suppression drugs.
Such a barrier needs to be selective in its permeability to allow
Gordon C. Weir passage of smaller compounds such as glucose, insulin, and
gordon.weir@joslin.harvard.edu amino acids to allow beta-cell survival and function, but at
1
the same time minimizing the entry of immune rejection medi-
Joslin Diabetes Center, 1 Joslin Pl, Boston, MA 02215, USA
ators. This has been accomplished by size exclusion and
50 Page 2 of 7 Curr Diab Rep (2018) 18: 50

manipulation of the membrane pore size. Not only must the molecules are similar in size as insulin and some are extremely
membranes limit the entry of damage-causing cells and medi- small, such as nitric oxide. Furthermore, pancreatic islets are
ators, but it may also be important for them to restrict what known to make inflammatory mediators such as IL-1β,
comes out of devices such as antigens and mediators that could IFN-γ, and MCP-1 [11]. Size exclusion by an encapsulation
provoke an inflammatory reaction. membrane is therefore not possible to prevent the entry of all
Most membranes are made with polymer chains that form immune mediators, even though many studies have focused
mesh networks, which contain torturous movement paths on ever-smaller pore sizes. It remains unknown as to how
through which molecules must traverse to cross the mem- much restriction is most optimal for encapsulating insulin-
brane. The size of these paths varies so any number deter- producing cells. However, it would appear that very small
mined for size exclusion can only be an estimate. In the ab- pores that prevent the entry of certain cytokines are not re-
sence of active fluid flow, molecules travel via diffusion and quired to protect islets from autoimmunity and allogeneic re-
this rate of entry is determined by the concentration gradient, jection. It has been demonstrated that TheraCyte devices that
the path size distribution, path lengths, molecular weight of are relatively porous, allowing even antibody entry, can pro-
the compound, and the electrochemical and polar interactions tect islets from sensitized rat allogeneic response [12]. A sim-
between the molecules and the polymer chains. In recent ilar device, Encaptra, demonstrated similar immune protection
years, more precisely defined pores on the nanometer scale [13]. Both studies also showed minimal antigen sensitization
have been produced with some biomaterials and can have and indirect T cell responses. A small number of case studies
better control of the permselectivity [10]. Regardless, many and pilot clinical trials also have demonstrated that encapsu-
encapsulation membrane materials have been used to capture lation can prevent immune rejection and autoimmune destruc-
this delicate balance of restricting the movement of molecules tion of allogeneic islet grafts in non-immunosuppressed pa-
to facilitate long-term islet survival and function in immune- tients. In 1994, Scharp et al. [14] reported that encapsulated
competent hosts. human islets remained viable when they were retrieved from
For the purpose of this review, macroencapsulation refers nine patients (three each of normal control, patients with T1D,
to retrievable devices that contain large numbers of and with T2D) 2 weeks after in vivo implantation. The com-
transplanted cells, such that only one or very few devices are pany Beta-O2 reported in two clinical studies that their βAir
needed to deliver a curative cell dose. This is distinguished macroencapsulation device allowed human islets to survive
from microencapsulation, in which small capsules, typically for over 6 month’s implantation in non-immunosuppressed
made of hydrogels such as alginate, contain only a few cell patients with T1D [15•, 16, 17]. At the 2015 IPITA Stem
clusters, meaning that many capsules would be needed to Cell Workshop, ViaCyte also reported a case study in which
deliver a therapeutic dose. Macroencapsulation devices have Encaptra containing allogeneic tissue derived from human
received renewed attention because of the availability of embryonic stem cells (hESCs) remained viable after spending
insulin-producing cell products derived from pluripotent stem many weeks in a patient with T1D. Additional clinical studies
cells. These devices have been considered as a safeguard to using alginate microencapsulated human islets without immu-
reduce the perceived risk of teratoma formation or other po- nosuppression reported measurable insulin output for several
tentially dangerous cells. This review will focus on the many months [18, 19]. The average exclusion sizes of some of these
requirements of a successful macroencapsulation system devices, 0.2–0.4 μm (βAir) and 0.45 μm (TheraCyte), are
while reviewing important discoveries and innovative designs large enough to allow entry of some antibodies and most cy-
toward this goal. tokines. Therefore, it seems likely that one can use relatively
porous macroencapsulation membranes to sustain islet cell
survival in humans, although we still do not fully understand
Requirements for a Successful Islet the protection mechanism.
Macroencapsulation Device Another important issue with membranes is their biocom-
patibility because inflammatory reactions elicited as a foreign
Protection from Immune Rejection and Autoimmune body response by membranes could produce potentially toxic
Destruction mediators and also lead to the formation of fibrotic tissue sur-
rounding the device, impeding the delivery of oxygen and nu-
It is generally thought that allogeneic graft rejection is primar- trients to the contained islet cells. It is possible that one does not
ily driven by direct T cell recognition of foreign antigens, need to worry about cytokines if cells can be kept well oxygen-
which requires direct contact by cytotoxic T cells with the ated with minimal stress. We know that islets release danger-
graft. The encapsulation membrane needs to keep out cell associated molecular patterns (DAMPs) leading to inflamma-
entry at a minimum. But there are additional immune rejection tory immune activation as may occur with impaired delivery of
mediators such as antibodies, complement, and cytokines that oxygen and nutrients to islet cells in a device [20]. Newly
may or may not be detrimental to graft survival. Some of these generated materials and our enhanced understanding of how
Curr Diab Rep (2018) 18: 50 Page 3 of 7 50

device geometry and size correlate with these responses have Glucose and Insulin Kinetics
produced encapsulation devices with improved biocompatibil-
ity [21–23]. However, as discussed below, progress on mini- In addition to the challenge of providing sufficient oxygen to
mizing detrimental immune responses alone is not sufficient for islets in a macrodevice, encapsulation presents another mass
a successful beta-cell macroencapsulation device. transport problem with the release of insulin. From native
islets, stimulated insulin secretion can enter the circulation in
Packing Density, Spatial Arrangement, and Oxygen large amounts within a few minutes, this being facilitated by
Requirements the rich vascularity of islets [26]. Equally important is the
ability of beta cells to rapidly shutoff insulin secretion at low
Enough functional beta-cell mass needs to be present to provide glucose concentrations. This rapid shutoff of insulin is partic-
adequate glucose control. Clinical islet transplantation suggests ularly important for defending against hypoglycemia. With
that > 5000 IEQ/kg will be required to correct human diabetes encapsulation, blood vessels are separated from islets by a
or approximately 350,000 IEQ for a 70-kg person. Packing this membrane, which means that glucose must diffuse a distance
many cells into a device with a reasonably small footprint is no of perhaps 50–400 μm to reach the beta cells. Because glucose
easy feat. The encapsulation membrane ensures that blood ves- is a small molecule, this might not cause much of a delay, but
sels can only be as close to the islets as the device outer surface, insulin being much larger is another story because it will dif-
so oxygen supply becomes a limiting factor for islet viability fuse much more slowly and will also meet resistance as it
and function—the oxygen concentration decreases from con- traverses the membrane. Thus, there is a major issue getting
sumption by the cells as it diffuses deeper into the device. Beta insulin rapidly into the circulation. Studies with perifusion of
cells can survive at very low oxygen tensions such as below capsules containing islets in vitro are misleading because the
2 mmHg, but insulin secretion falls off severely with only mod- flow provided by perifusion greatly facilitates the delivery of
est hypoxia, such as below 30 mmHg [24]. Native islet pO2 is insulin through a membrane [27], leaving only minor blunting
approximately 40 mmHg. Therefore, it is imperative to keep of the profile of insulin secretion. However, when islets are
the oxygen supply high enough to sustain mass and function. contained within a macrodevice in vivo, the speed of insulin
This has led to mostly thin and planar designs of movement for a distance of several hundred microns from host
macroencapsulation devices, which try to optimize the vasculature is dependent upon diffusion through a liquid mi-
surface-to-volume ratio to minimize the diffusion distance be- lieu that has little flow. This is a problem for all diffusion-
tween host vasculature and islets. Mathematical models suggest based encapsulation systems whether they are small alginate
that the highest density that can be achieved with an alginate- beads or macrodevices. Macroencapsulated islets in alginate
based planar macroencapsulation device containing 50-μm beads 3 mm in diameter have been shown to normalize glu-
small islet aggregates without incurring significant hypoxia is cose levels in rats, but when the rats are infused with glucose
approximately 760 IEQ/cm2 [24], which translates to 460 cm2 and arginine, there is almost no increase in circulating insulin
for 350,000 IEQ, a size that starts to challenge clinical practi- levels over a period of more than an hour [28]. In other exper-
cality. Increasing the packing density, however, will predictably iments using smaller alginate beads of about 800 μm in diam-
lead to hypoxic regions that are furthest away from the mem- eter, diabetes in rats could be reversed, and with an intrave-
brane, and detrimental to islet viability and function. One ap- nous glucose tolerance test (IVGTT), the glucose could be
proach by the company Beta-O2 is to provide exogenous oxy- cleared, but there was almost no increase of circulating C-
gen daily via a port to support a higher islet density at 1400– peptide over a period of more than an hour. Moreover, the rats
3600 IEQ/cm2, although it is not clear how well this density can developed hypoglycemia when exercised [29]. The clinical
be maintained over time. Others have developed in situ- report on βAir containing human islets in a patient with
generated oxygen to increase local oxygen concentration [25], T1D showed blunted and slow stimulated C peptide response
but this approach can only supply oxygen for a finite period, at very low concentrations [30]. More attention has been paid
beyond which the implanted islet mass still has to rely on host to assessing of appropriate insulin response kinetics recently
vascularization to survive. Slightly enhanced oxygen transport [31•, 32], pointing out that measuring simply glycemia or
rate across the membrane through the use of perfluorocarbon glucose clearance after a challenge does not reflect whether
has also been attempted but the basic physics limitation remains the encapsulated islet cells secrete insulin in a physiological
[24]. In short, oxygen greatly limits the packing density of fashion. In the extreme case, streptozotocin-induced diabetic
diffusion-based macroencapsulation devices but might be over- mice implanted with insulin pellets displayed normal glucose
come with strategies to provide exogenous oxygen and increas- clearance during an IVGTT but produce negligible C-peptide
ing surface-to-volume ratios of the device design. Therefore, [32]. The implication for most islet encapsulation study is
there is now good evidence that islet cells can survive for long important because most reports equate the amelioration of
periods of time in macrodevices, but providing adequate pack- hyperglycemia with presumed good islet function, while only
ing density continues to be a difficult challenge.
50 Page 4 of 7 Curr Diab Rep (2018) 18: 50

very few studies have actually examined the dynamic C- on macroencapsulated cell phenotype, turnover, and
peptide or insulin response. compositions.
The delayed release of insulin from devices may lead to
dangerous hypoglycemia when encapsulated islets are used as
a treatment for diabetes. There may well be enough insulin Site of Implantation and Integration with Host Tissue
produced to keep glucose levels in a near normal range but a
meal may pose a problem. For example, with a high carbohy- Due to the large size of macroencapsulation devices, there
drate meal, the glucose should reach the encapsulated beta are only a few locations in the human body that can ac-
cells in just a few minutes and stimulate insulin secretion, commodate them. The most attractive locations are the
which means there will be a lot of insulin within the device. subcutaneous space, the omentum, intra-peritoneum, and
The increase of glucose caused by the meal will be reasonably pre-peritoneum. The subcutaneous space is the most sur-
well cleared because there had been enough insulin before the gically accessible and least invasive. The portal drainage
meal to keep the glucose uptake mechanisms active. The dan- of omental and intra-peritoneum sites could in theory pro-
ger comes as the large amount of insulin in the device diffuses vide more physiological insulin delivery. Richer vascular
out over perhaps hours when a subject is not eating or could density in the omentum and the pre-peritoneum should
even be exercising or sleeping. offer better mass transport conditions. General biocompat-
ibility of the device geometry and material is necessary to
avoid inflammatory and fibrotic responses. These detri-
Supporting Beta-Cell Phenotype and Containing mental responses can lead to fibrotic overgrowth on the
Unwanted Cells device, choking off delivery of oxygen and other nutrients
to the islets, further impairing insulin production. Ideally,
Rationales for using macroencapsulation devices are that they the device surface should be well vascularized by host
can contain potentially dangerous cells and they can be re- vessels with minimal fibrosis. Thus, outcomes depend up-
trieved if there was some untoward reaction. There is a poten- on a complex interplay between implantation site, device
tial risk of teratoma formation from undifferentiated cells in the design, islet quality, and the wound healing response. An
cell products generated from pluripotent stem cells, and the optimized transplant methodology should therefore con-
conventional wisdom is that an effective macroencapsulation sider the design of the macroencapsulation and tailor the
device can minimize the risk of cells escaping. Few reports transplantation site to achieve appropriate integration with
have directly tested this assumption. It was demonstrated that the host vasculature and tissue while allowing the main-
a nanoporous macroencapsulation device successfully con- tenance of sufficient beta-cell mass.
fined teratomas arising from hESCs when implanted into im-
munodeficient mice, while unencapsulated cells placed under
the kidney capsule quickly grew throughout the peritoneal
cavity [10]. Recent and Current Clinical Studies
A less well-understood aspect of macroencapsulation is
the turnover and maintenance of beta-cell mass and func- There has been only limited clinical testing of macroencapsulated
tion within the device. It was demonstrated that different islet products in a small number of patients. Table 1 below
encapsulation systems containing hESC-derived pancreat- summarizes recent studies. Only Beta-O2 has published
ic progenitors yielded vastly different maturation out- clinical results [15•, 30], while other researchers had oral
comes—mostly alpha cells in alginate microcapsules and presentations at public meetings. It is encouraging that all
substantial numbers of beta cells in a macrodevice [33]. appeared to have good safety signals without serious ad-
The same group recently reported that the same verse events. Beta-O2 loaded 4600 IEQ/kg cadaveric hu-
macroencapsulated cell population continued to mature man islets within two βAir devices, although the reports
over 6 to 12 months toward more mature beta-cell pheno- did not quantify whether the islet and beta-cell mass was
type resembling primary human beta cells in terms of maintained throughout the implantation period. ViaCyte’s
beta-cell number, insulin content, and insulin response cell population is progenitors that were reported to have
per beta cell; meanwhile, the ratio of alpha to beta cells great proliferative capacity and can undergo significant
substantially changed from 1:2 to 2:1 at 6 and 12 months population turnover post-transplant, so it is not clear what
[34•]. This is very different than when these hESC-derived mature beta-cell mass is produced in humans. Overall,
progenitors were transplanted without encapsulation into what remains to be seen is whether one can maintain the
the epididymal fat pad or under the kidney capsule, where therapeutic beta-cell mass in these devices, and whether
they matured into functional beta cells [35]. Clearly, much these cells can function physiologically in these devices
more research is needed to determine the long-term effects as described above.
Curr Diab Rep (2018) 18: 50 Page 5 of 7 50

Table 1 Current and recent clinical trials of macroencapsulated islet/beta cells

Description Status Patient population ClinicalTrials.gov number

ViaCyte, multiple VC-01, a macroencapsulation Enrollment complete T1D NCT02239354


clinical sites device containing hESC-derived and in follow-up phase NCT02939118
pancreatic progenitors placed
under the skin
ViaCyte, multiple VC-02, which is VC-01 but with Enrolling T1D with hypoglycemic NCT03163511
clinical sites the device punctured with holes unawareness NCT03162926
placed under the skin, administered
with immunosuppression
Βeta-O2 and Uppsala βAir Teflon and alginate encased Active but not enrolling T1D NCT02064309
University cadaveric human islets with
exogenous oxygen supply, placed
under the skin

Future Outlooks and Overcoming recruitment and associated cytokines during this process prior
Macroencapsulation Limitations to being re-connected with the host vasculature [39]. Several
groups have reported the utility of pre-vascularization of emp-
Provide Convection to Improve Mass Transport ty devices prior to filling them with islets [40, 41]. The
established vascular network should in theory provide an in-
Given the mass transport limitations discussed above for creased oxygenated environment and help with islet survival.
diffusion-based macroencapsulation devices, a number of re- Additionally, novel device designs aim to increase surface-to-
searchers developed intravascular devices with convective volume ratio to further improve oxygen and nutrient exchange
fluid flow. In fact, much success was reported in the 1990s between implanted cells and host tissue. An et al. took inspi-
that demonstrated long-term allo- and xenogeneic islet surviv- ration from alginate microcapsules’ high surface-to-volume
al in rodents and dogs [36]. Such device designs required ratio and designed a string-shaped device [42], while Gurlin
anastomosis to the blood vessels, and the fluid flow past the et al. created slits within a polymer sheet to induce orthogonal
semipermeable membrane significantly enhanced transport to vasculature through the device plane [43]. However, it is not
the islet compartment. The advantages included improved clear whether such modifications can still create the packing
packing density, kinetics of oxygen, glucose, and insulin; the density needed for clinical application.
disadvantages include surgical complications, blood biocom- It would be remiss to neglect some complementary scaffold
patibility, and the risk of bleeding. In fact, such a device was technologies that seek to enhance islet engraftment and graft
very close to a clinical trial, but the project was terminated retrieval but without the physical barrier for immune protec-
after a transplanted dog died from rupture at the vascular con- tion [44], meaning that immunosuppression would still be
nection and bleeding. However, such intravascular devices required. These kinds of scaffold technologies aim to create
might warrant a second look now, given our better understand- a (pre-)vascularized space for islet infusion, and sometimes
ing of blood biocompatibility and improved biomaterials. Roy with a non-biodegradable scaffold for easy graft removal.
et al. have reported a device design that utilizes the blood flow The company Sernova has reported proof of concept islet
pressure difference to drive ultrafiltrate across the semiperme- transplant animal studies using their Cell Pouch System [45]
able membrane around the islets [37]. Other research groups and a small pilot clinical study using cadaveric human islets
are exploring a variety of different approaches to pump inter- [46]. The Edmonton group has taken this concept and used a
stitial fluid past islets. removable catheter approach to promote engraftment of
mouse, human islets, or hESC-derived progenitors [47, 48].
Although the initial human study using the Sernova Cell
Improve Vascularization and Increase
Pouch reported minimal beta-cell function [46], this type of
Surface-to-Volume Ratio for Diffusion-Based Devices
approach could be complementary to macroencapsulation by
improving vascular density at the subcutaneous site.
For diffusion-based devices, one must try to maximize the
transport properties across membranes. Surface treatment with
controlled release of compounds such as VEGF might lead to Assess Functional Beta-Cell Mass and Insulin Kinetics
increased vascularization [38]. The inflammatory response af- in more Detail
ter surgery and islet implantation is a key process for vascu-
larization. However, islets can suffer from low oxygen and While much progress has been made in improving biomaterial
also potentially damaging effects from inflammatory cell compatibility, providing oxygen supply, and demonstrating
50 Page 6 of 7 Curr Diab Rep (2018) 18: 50

safety and immune protection of macroencapsulation devices, 3. Thompson DM, Meloche M, Ao Z, Paty B, Keown P, Shapiro RJ,
et al. Reduced progression of diabetic microvascular complications
the research community needs to more critically assess wheth-
with islet cell transplantation compared with intensive medical ther-
er the implanted cells can effect physiological insulin secre- apy. Transplantation. 2011;91(3):373–8.
tion in the host. Frequent sampling of C peptide or insulin 4. Thompson DM, Begg IS, Harris C, Ao Z, Fung MA, Meloche RM,
after glucose stimulation should be a necessary test for all et al. Reduced progression of diabetic retinopathy after islet cell
transplantation compared with intensive medical therapy.
device studies in vivo. Quantification of actual and functional
Transplantation. 2008;85(10):1400–5.
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release from these devices create a risk for hypoglycemia and Wernerson A, et al. The TheraCyte device protects against islet
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tion of allogeneic mouse pancreatic progenitor cells by a
Compliance with Ethical Standards macroencapsulation device. Transplantation. 2016;100(6):1211–8.
14. Scharp DW, Swanson CJ, Olack BJ, Latta PP, Hegre OD, Doherty
Conflict of Interest Albert J. Hwa serves on the SAB of Beta Cell NV EJ, et al. Protection of encapsulated human islets implanted without
and serves as a consultant for Sigilon Therapeutics. immunosuppression in patients with type I or type II diabetes and in
Gordon C. Weir serves on the SAB of Semma Therapeutics and Beta- nondiabetic control subjects. Diabetes. 1994;43:1167–70.
O2. 15.• Carlsson PO, Espes D, Sedigh A, Rotem A, Zimerman B, Grinberg
H, et al. Transplantation of macroencapsulated human islets within
Human and Animal Rights and Informed Consent This article does not the bioartificial pancreas beta air to patients with type 1 diabetes
contain any studies with human or animal subjects performed by any of mellitus. Am J Transplant. 2017; https://doi.org/10.1111/ajt.14642.
the authors. This study shows that a macroencapsulation device with a
relatively large pore size and exogenous oxygen supply can
provide immune protection to allogeneic islets in non-
immunosuppressed patients with T1D, but the kinetics of insu-
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