ASAIO Journal 2021 Review Article

The Current Status of Bioartificial Pancreas Devices

SARA J. PHOTIADIS , REBECCA C. GOLOGORSKY , AND DEEPIKA SARODE

Type 1 diabetes mellitus is a common and highly morbid di- blood glucose would allow type 1 diabetic patients to have
sease for which there is no cure. Treatment primarily involves an excellent quality of life free from multiple hospitalizations,
exogenous insulin administration, and, under specific circum- end-stage organ failure, and early mortality.5
stances, islet or pancreas transplantation. However, insulin The bioartificial pancreas (BAP) is a solution that could pro-
replacement alone fails to replicate the endocrine function vide the tight metabolic control needed to manage type 1 di-
of the pancreas and does not provide durable euglycemia. In abetes.6 Multiple devices are currently in preclinical or early
addition, transplantation requires lifelong use of immunosup- clinical studies.7–9 although numerous reviews have discussed
pressive medications, which has deleterious side effects, is encapsulation strategies and insulin-producing cell sources,10,11
expensive, and is inappropriate for use in adolescents. A bio- none have offered a quantitative comparison of device func-
artificial pancreas that provides total endocrine pancreatic tion. We give an overview of the currently available treatments
function without immunosuppression is a potential therapy for type 1 diabetes, the current bioartificial pancreas devices,
for treatment of type 1 diabetes. Numerous models are in de- and provide a quantitative comparison between devices that
velopment and take different approaches to cell source, en- will inform future BAP design.
capsulation method, and device implantation location. We
review current therapies for type 1 diabetes mellitus, the Part I: Current Therapies for Type 1 Diabetes Mellitus
requirements for a bioartificial pancreas, and quantitatively
compare device function. ASAIO Journal 2021; 67:370–381.
Exogenous Insulin Therapy
Key Words: bioartificial pancreas, beta cell, islets of Langer- Exogenous insulin therapy is the primary treatment for
hans, type 1 diabetes mellitus, encapsulation T1DM.12 However, the complex interplay between multiple
endocrine hormones that controls glucose homeostasis can-
Type 1 diabetes mellitus (T1DM) is a common and difficult not be reproduced by insulin therapy alone. As such, patients
managed with exogenous insulin therapy experience frequent
to treat disease associated with high morbidity and early mor-
tality.1 The condition is caused by autoimmune destruction of episodes of acute hypoglycemia and hyperglycemia.13 The
insulin-producing β cells within the pancreas, resulting in dys- resulting blood sugar dysregulation can lead to serious com-
regulation of blood glucose levels. The events triggering β-cell plications, such as diabetic ketoacidosis (DKA), and death.14
death are poorly understood but are thought to be a combina- In the long term, hyperglycemia causes microvascular disease
tion of genetic and environmental insults. There are 1.25 mil- resulting in retinopathy, peripheral vascular disease, end-stage
lion people in the United States living with T1DM, and greater renal disease, and cardiovascular disease, which are the major
than 20 million people worldwide.2 By 2020, it is estimated causes of morbidity and mortality of T1DM.15 Technology that
that one out of 300 adolescents living in the United States will enables maintenance of strict glucose homeostasis is necessary.
be diagnosed with T1DM.3 An evolving method for treating patients with T1DM is infu-
The primary treatment of T1DM is exogenous insulin admin- sion of physiologic basal levels of insulin and bolus dosing for
istration. Although insulin therapy prevents early mortality, its food intake via an insulin pump paired with a continuous glu-
use does not guarantee euglycemia. Long-term fluctuations cose monitor that calculates insulin requirements according to
in blood glucose levels despite insulin administration ulti- blood glucose levels.16 Although insulin pumps have resulted
mately results in multiorgan dysfunction.4 Frequent fluctua- in increased glycemic control, there are several problems with
tions in blood glucose lead to the complications of diabetes insulin pumps, including mechanical and electrical malfunc-
and resulting organ failure. Obtaining physiologic control of tions of the pump and infusion system, cutaneous infections
and scarring, and imperfect blood glucose regulation, poten-
tially resulting in immediately life threatening hyper- or hypo-
From the Department of Bioengineering and Therapeutic Sciences, glycemia.17,18 One prospective study reports an adverse event
University of California at San Francisco, San Francisco, CA.
Submitted for consideration February 2020; accepted for publica-
rate of 40 per 100 person-years, with the most common ad-
tion in revised form June 2020. verse events being hyperglycemia and DKA requiring hospi-
Disclosure: The authors have no conflicts of interest to report. talization.19 Additionally, this technology is expensive and
Correspondence: Sara J. Photiadis, Department of Bioengineering requires a high level of patient education and compliance.20
and Therapeutic Sciences, University of California at San Francisco, When insulin pumps are not an adequate or attainable solu-
San Francisco, CA. Email: [email protected].
Copyright © 2020 The Author(s). Published by Wolters Kluwer tion for diabetes management, pancreas transplantation is the
Health, Inc. on behalf of the ASAIO. This is an open-access article treatment of choice.
distributed under the terms of the Creative Commons Attribution-Non
Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is Pancreas Transplantation
permissible to download and share the work provided it is properly
cited. The work cannot be changed in any way or used commercially There are many problems preventing widespread usage of
without permission from the journal. pancreas transplantation for the treatment of T1DM. Organ
DOI: 10.1097/MAT.0000000000001252 scarcity, complexity of the operation, posttransplant morbidity,

370
 ADVANCES IN BIOARTIFICIAL PANCREAS 371

Figure 1. Bioartificial pancreas concept: Islets or islet-like cells surrounded by a semipermeable, immune-protective barrier (dotted line).
Small molecules, including oxygen, glucose, and insulin, can freely cross the barrier while large immune system components are prevented
from infiltrating the barrier. Potential islet sources include human adult islets, stem cell–derived beta-like cells, beta cells derived from
induced-pluripotent stem cells, and xenogeneic sources.

and immunosuppression are significant barriers to pancreas and the immunosuppressive requirements.6 The protective barri-
transplantation.21 Lifelong immunosuppression causes direct ers of a bioartificial pancreas device are thought to promote islet
toxicity to the heart, kidneys, and gastrointestinal tract.22 The longevity and result in long-term endocrine function.11
resulting immune dysfunction increases the risk of infection
and malignancy,23 rendering immunosuppression dangerous
Part II: Engineering a Bioartificial Pancreas
for any patient and specifically precludes their use in the pe-
diatric population. Furthermore, at greater than 10 years post- The bioartificial pancreas comprises insulin-producing cells
transplant graft function declines to less than 50%.24 surrounded by semipermeable encapsulating membranes31
(Figure 1). The design of a bioartificial pancreas is informed by
Clinical Islet Transplantation the architecture of the human pancreas and islet physiology, as
mimicking the natural islet environment in a BAP device will in-
Percutaneous clinical islet cell transplantation (CIT) is an crease the chance of successful long-term device function. After
endovascular procedure involving injection of purified islets implantation, the pancreatic graft requires adequate oxygena-
into the portal vein, which then migrate to and ultimately re- tion, exchange of stimulants and products, and protection from
side in the liver.25 Since the first islet cell transplant was per- immune rejection,32 which can be achieved by optimizing the
formed in 1999, more than 1,500 patients have undergone the encapsulation strategy, cell source, and implantation location.33
procedure.26 In a multinational phase III, clinical trial involv-
ing 48 patients with severe hypoglycemic unawareness, 87.5%
Islet Physiology
and 71% of patients maintained near-euglycemia at the one
and two year mark, respectively.27 Scattered throughout the pancreas are 70–250 μm-diameter
Although islet transplantation has achieved success in spheroid structures called the islets of Langerhans34 (Figure 2).
obtaining glycemic control, there are major drawbacks to the The islets are composed of multiple cell types, including beta
procedure. The instant blood mediated inflammatory reaction cells that produce insulin, alpha cells that produce glucagon,
(IBMIR) is characterized by the host’s innate immune system delta cells that produce somatostatin, and PP cells which pro-
attacking the newly implanted cells, which drastically reduces duce polypeptide protein. Endocrine cells only comprise 1–2%
the number of transplanted islets.28 Antiinflammatory agents, of the pancreas by volume,35 but use between 5 and 20% of
such as anti-TNF alpha biologics and IL-1 antagonists, have the flow depending on metabolic needs36 (Figure 3). Each islet
been used in an effort to dampen this response with incon- is fed by two or three afferent arterioles, and, within the islets,
sistent success.29,30 Equally detrimental is the need for lifelong the arterioles become highly fenestrated.37 The complexity of
immunosuppression after islet cell transplantation.22 islet blood supply suggests a highly tunable system in which
The medical and scientific community is developing the bioar- the amount of blood flow is modulated at the level of the feed-
tificial pancreas, with the goal of delivering the same therapeutic ing arteriole based on metabolic needs. During the process of
benefit of clinical islet transplantation. Bioartificial pancreas islet isolation, the blood supply to islets becomes deranged,38
devices offer distinct advantages over percutaneous islet cell undoubtedly affecting their functionality in medical devices.
transplantation. The cells are protected within an immune-pro- Restoring islet nutrient supply is central to long-term device
tective environment, which eliminates both the IBMIR response function and success in treating T1DM.
372 PHOTIADIS ET AL.

Figure 2. Pancreas anatomy: The elongate pancreas abuts the small intestine. Islets of Langerhans, which number roughly 500,000–1 mil-
lion islets in a human, are distributed evenly throughout the pancreas.

Cell Sources for the Implanted Bioartificial Pancreas an opportunity to create islet-like cells given the presence of
the GLUT two glucose transporter and the glucose phosphory-
Because the number of islets within a human pancreas
lating protein, glucokinase. These two elements are essential
ranges from several hundred thousand to millions,37 there is
for sensing changes in blood glucose and the secretion of in-
a need for alternative sources of islets for a bioartificial pan-
sulin granules. Lawandi et al.48 demonstrated the use of Mel-
creas. Organs scarcity and the costly specialized centers nec-
ligen cells, or human hepatocyte-derived islet-like cells, in the
essary for islet isolation and purification preclude adult human
maintenance of normoglycemia in the diabetic mouse model.
pancreases from being a source for islets.39 Alternate sources
The significant limitation toward human use of Melligen cells
of islets and islet-like cells ease reliance on cadaveric islets,
is that the cells continue to proliferate, risking tumorigenesis
which are scarce and potentially compromised depending and eventual hypoglycemia. Despite these risks, Melligen cells
on the donor’s comorbidities and cause of death. Among the offer tremendous potential as a beta-cell source, and Pharma-
contenders are beta-like cells derived from human pluripotent cyte, Inc., is developing encapsulating technology using hepa-
stem cells such as embryonic and induced-pluripotent stem tocyte-derived cells.
cells, human hepatocyte-derived islet-like cells, and xenoge- Ultimately, the use of a renewable cell source or islets from
neic sources.40 xenogeneic islet sources is essential to making the bioartificial
Two promising beta-cell sources are differentiation from pancreas device a reality for patients with T1DM.
human embryonic stem cells (hESC) and human induced-plurip-
otent stem cells (hiPSC).41,42 The differentiation of pancreatic en-
Islet Encapsulation Strategies: Macroencapsulation,
docrine cells from embryonic stem cells is a multistep pathway
Microencapsulation, and Nanoencapsulation
tightly regulated by the introduction of signaling molecules43
(Figure 4). Agulnick et al.44 demonstrated success at differentiat- Encapsulation strategies employing durable selectively per-
ing highly enriched pancreatic endocrine cells in a seven-step meable membranes that allow free exchange of nutrients and
process that has shown efficacy in reversing diabetes in a mouse exclude immunocytes and antibodies are central to achieving
model. Human pluripotent stem cells are particularly appeal- the requirements for a bioartificial pancreas. The three encap-
ing as they can be derived from human somatic cells, such as sulation strategies used in BAP devices are macroencapsula-
skin fibroblasts.45 Early studies demonstrate that beta-like cells tion, microencapsulation, and nanoencapsulation49 (Figure 5).
derived from hiPSC have reversed hyperglycemia in a diabetic Macroencapsulation devices are several centimeters in diam-
mouse model.46 Although successes have been achieved, there eter and are made of hollow fibers, flat sheets, or disks, and
are still significant barriers to human implementation, including they contain a central chamber which houses islets. It is es-
scalability, immune protection of the cells, exclusion of polyhor- sential that macroencapsulated devices are well-perfused with
monal cell types, and maximizing phenotypically normal beta- little internal dead space, and that fibroblastic growth on the
like cells that response to glucose stimulation.47 device is minimized to allow efficient transfer of substances.50
An alternative cell source is derivation from other human so- The primary constraint on macroencapsulated devices is
matic cells, such as hepatocytes. Human hepatocytes provide achieving the ideal diffusion distance between oxygen source
 ADVANCES IN BIOARTIFICIAL PANCREAS 373

Figure 3. Islet of Langerhans physiology: Each islet is approximately 75–200 microns in diameter and is surrounded by multiple different
cell types, including immune cells, vascular cells, stromal cells, and neural cells. Each islet is supplied by two to three arterioles, which branch
into capillaries within the islet, supplying a rich vascular inflow.

and islet, which is approximately 200 µm.51 Multiple macroen- concepts surrounding islet encapsulation is relative hypoxia
capsulated devices are in advanced preclinical or early phase and central necrosis within the islet if diffusion distances are
human clinical trials8,44,52,53 (Table 1). too great.55 Microencapsulated islets have shown efficacy in
Microencapsulation techniques involve individually encap- small animal models but have shown limited efficacy in non-
sulating islets with micrometer thick layers of biocompatible human primates.56–58 The most significant study published
porous materials, such as hydrogels.54 Coated islets are then demonstrated the effectiveness of alginate microencapsulated
infused into the body, most commonly into the intraperitoneal islets in streptozotocin-induced diabetic nonhuman primates
cavity. The primary constraints on microencapsulated islets with immunosuppression.59 Normoglycemia was achieved
are that exchange of substances is governed by diffusion and immediately following transplant, and insulin independence
local concentration gradients of insulin and glucose and the was maintained for three to four days. Plasma C-peptide levels
immune response to the pancreatic graft. One of the limiting were detectable until postoperative day 10 when they rapidly

Figure 4. Beta-cell differentiation: The differentiation of beta-like cells from human ESC is a four-step process. The resulting beta-like cell
mass is immature requires further refinements to adequately respond to glucose stimulation. ESC, embryonic stem cells.
374 PHOTIADIS ET AL.

Figure 5. (A) Macroencapsulation: In this encapsulating strategy, a group of islets or islet-like cells are suspended within a supportive, po-
rous scaffold, and encapsulated within a semipermeable layer and a protective outer housing. (B) Microencapsulation: In this encapsulating
strategy, an islet or islet-like cell is coated with micrometer thick, porous, biocompatible materials such as a hydrogel. If the coating is >800
µm, the cells in the center of the islet are deprived of oxygen, and necrosis occurs. (C) Nanoencapsulation: In this encapsulating strategy,
individual islets or islet-like cells are coated with multiple layers that are nanometers thick in a process called conformal coating.

diminished. While there was minimal inflammatory response, poor diffusion of nutrients and insulin within the device due
there was significant islet necrosis resulting from hypoxia. to large (>200 µm) diffusion distances.51 This results in poor
Nanoencapsulation, or conformal coating, is similar in con- glucose-insulin kinetics and, ultimately, islet cell death. Addi-
cept to microencapsulation but involves layer by layer dep- tionally, subcutaneous implantation stimulates a brisk foreign
osition of nanoscale layers of biocompatible materials.60 This body response initiated by macrophage migration to the af-
approach generates a coating that is nanometers thick, the goal fected area followed by macrophage fusion into foreign body
of which is to limit the diffusion distance to the islet within. giant cells, ultimately resulting in fibrosis,8,53,64 which increases
This technique has shown success in small animal models61 the diffusion distance. Accordingly, there is a strong effort to
but has not been tested in primates. modify current devices to address poor vascularization for
which the primary strategies are induction of neovasculariza-
tion, implantation into a highly vascularized location, and di-
Location
rect infusion of oxygen.
The combination of cells with nutrient-rich housing scaf- The intravascular location is an alternative implantation lo-
fold and barrier membranes results in a bioartificial pancreas. cation. Arterial blood allows efficient exchange of nutrients
Regardless of whether the structure is a macro- or micro- while preventing local accumulation of molecules that elim-
structure, the implantation location is equally important. The inate concentration gradients.65 The most important limita-
devices can be implanted extravascularly or intravascularly.62 tions to an intravascular device are the complexity of surgery
Ease of implantation, retrievability, and proximity to nutrient involved, the lack of retrievability, and the risk of thrombotic
source are the main factors to assess when choosing an im- and hemorrhagic complications.66–69 However, improvement
plantation location. in vascular surgery techniques and anticoagulation strategies
Extravascular implantation in subcutaneous tissues is attrac- using medications is reinvigorating interest in the development
tive in its surgical practicality, removal, replenishment, and of an intravascular bioartificial pancreas device. Recently, Roy
avoidance of vital organs.63 Conversely, low surface area to et al. described the feasibility of an intravascular implantation
volume ratio, poor vascularization, and diffusion constraints of a BAP developed using microelectromechanical systems
limit islet performance. The geometry of extravascular devices technology; however, there is limited data on glucose-insulin
and the relative avascular location of implantation leads to kinetics in vivo.70,71
 Table 1.  Summary of Results from Device Preclinical and Clinical Testing.

Trial/ IEQ/kg Body Decreased Study

Manufacturer, Animal Weight Implant Insulin Basal C-peptide Duration
y Model, n Islet Type Transplanted Location Needs Levels Inflammatory Response (mo) Findings

CIT-O7 trial Humans, 48 Adult human 11,982 Liver Yes Physiologic Donor-specific antibody 24 1. 87.5% patients achieved primary
(Edmonton islets formation end point: HbA1c < 7% at day 365
protocol) and no SHE after day 28
201673 2. Insulin independence was
achieved by 52.1% by day 365
3. 42% remained insulin independent
at 730 d
Viacyte SCID/beige hESC N/A Subcutaneous N/A Physiologic and N/A 6 1. Pancreatic endocrine cells derived
201544 mice, five derived supratherapeutic in vitro function in vivo
cohorts cohorts 2. Cryopreserved pancreatic
endocrine cells function in vivo
3. Cells do not begin to function until
8 weeks
DRC, NSG mice, 17 hESC 2 × 108 Subcutaneous N/A Supratherapeutic N/A 11.5 1. Sustained basal C-peptide levels
Brussels, derived over 50 wks
Viacyte, 2. 26% of implants achieve c- peptide
Beta Cell levels > 6 ng/mL by week 20
Therapy 3. Cell loss at week 50 varied
Consortium between 3% and 87% between
201871 devices. Beta cell number varied
between 15,000 and 600,000.
DRC Nestle SCID beige hiPSC 1.2 × 108 or Subcutaneous N/A Physiologic and N/A 4.6 1. The use of a preformed pouch
macrosheet, mice, 58 derived 6 × 108 supratherapeutic was associated with increased
Beta Cell cohorts C-peptide release from the
Therapy implant
Consortium 2. Increase in cell mass did not result
201952 in increases basal or stimulated
C-peptide secretion
University of Mongrel IPCs derived 5 × 106 Rectus Sheath No Subtherapeutic Pericapsular fibrous 18 1. Fasting euglycemia in 4/6 dogs
Mansoura, diabetic from capsule with cellular within 8 weeks
ADVANCES IN BIOARTIFICIAL PANCREAS

Theracyte dog human infiltrate that was 2. Sustained subtherapeutic basal c

device model, 6 bone- strongly cell mediated peptide levels over a period of 6 mo
201853 marrow CD3+. No CD20+ cells 3. The % IPC increased from 3% to
MSC 22% after 6 mo in vivo
Beta Air Streptozotocin- Rat islets 6,556 Subcutaneous Yes Physiologic Implantation site had thin, 3 1. Normoglycemia achieved for 60 d
201372 induced vascularized fibrotic using xenogeneic rat islet
diabetic tissue. No evidence 2. The membranes prevented
minipigs, 8 of serum antirat Ab. leakage of rat antigens into the pig
Membranes impermeable serum and prevented diffusion of
to C1q or IgG pig IgG and C1q
Beta Air Type 1 diabetic Adult human 2,000-4,000 Subcutaneous No Subtherapeutic Nonadherent thin fibrotic 6 1. Fasting C peptide levels were
20178 human, 4 islets tissue surrounding increased for 8 weeks post
the device. Increase transplantation
in CD45+ cells, most 2. No HLA Ab response to islets
of which were CD 68+ 3. Inflammatory, fibrotic response to
macrophages, and the device
CD8+ cells 4. Transplantation did not result in
decreased insulin needs
(Continued)
375
 376 PHOTIADIS ET AL.

Part III: Analysis of Current Bioartificial Pancreas Devices

Quantitated basal and stimulated C-peptide and blood glucose levels shown in Figures 7–9, when available. CIT, clinical islet cell transplantation; DRC, Diabetes Research Center; hESC,
carrying the risk of hypoglycemia
normoglycemia from day 19–27
2. Melligen cells proliferate in vivo
1. Xenogeneic transplant function
There are several bioartificial pancreas devices that have

3. Melligen cells are resistant to

without immunosuppression
undergone rigorous preclinical and clinical testing including

1. Melligen cells maintained

2. Failure to achieve insulin
Viacyte’s Encaptra device (ViaCyte, Inc., San Diego, CA), the
Diabetes Research Center’s (DRC) planar macro-sheets devel-
Findings

cytokine destruction
and tumorigenesis
oped by Nestle Research, Lausanne, Switzerland, βO2 Tech-
nologies’ βAir device (βO2 Technologies, LTD., Rosh Haayin,
independence

Israel), and Theracyte’s BAP device (TheraCyte Inc., Laguna

Hills, CA) (Figure 6). The four devices are extravascular, subcu-
taneous devices, and have shown efficacy in reducing insulin

human embryonic stem cells; hiPSC, human induced pluripotent stem cells; IPCs, insulin-producing cells; MSC, mesenchymal stem cell; N/A, not applicable.
dependence in animal models. Comparing basic measures of
device functionality such as basal and stimulated C-peptide
Duration

levels, islet load, and glucose-insulin kinetics exposes the

Study

(mo)

shortcomings of each design and will inform future iterations

6

of the BAP. Details of device design and testing may be found

thin, vascularized fibrous

in Table 1.
cytokine exposure, Huh7
capsule. No CD8, CD3,
Inflammatory Response

cells were nonfunctional

response unaffected by

A bioartificial pancreas device must secrete insulin within

Implantation site had a

CD68 rarely present

physiologic ranges to cure T1DM. Two devices have achieved

Melligen cell insulin

when exposed to

both basal and stimulated C-peptide levels within the physio-

logic range: Viacyte’s Encaptra device using reaggregated (RA)
ESC-derived insulin-producing cells (IPCs) and DRC planar
cytokine

sheets using iPSC-derived IPC’s44,52,71 (Figure 7). βAir’s device

used in a porcine model demonstrated normal basal C-peptide
levels but stimulated values were not measured.72 These studies
Basal C-peptide

demonstrate that a BAP device can secrete clinically relevant

Supratherapeutic

levels of C-peptide and levels comparable to those measured

Levels
Table 1.  (Continued)

in the phase 3 CIT cohort.73

Multiple devices show either subtherapeutic or suprath-
erapeutic levels of basal and stimulated C-peptide. Subthera-
N/A

peutic C-peptide levels were seen in Theracyte’s device using

mesenchymal stem cell (MSC)-derived IPC’s and in βAir’s de-
Decreased

Needs
Insulin

vice using allogenic human islets in a human clinical trial8,53,74

Yes

N/A

(Figure 7). The poor function of Theracyte’s device may be

secondary to low numbers of functional IPCs whereas βAir’s
device’s subtherapeutic function is secondary to a low number
Subcutaneous

Subcutaneous

of islets. While subtherapeutic levels of C-peptide are undesir-

able, more work is needed to understand the potential delete-
Location
Implant

rious effects of supratherapeutic levels of C-peptide. Levels of

C-peptide that are inappropriately elevated, if proportional to
insulin concentrations, could have disastrous consequences in
vivo such as unintentional hypoglycemic episodes.75 Viacyte’s
Transplanted
IEQ/kg Body

Encaptra device using PEC-01 cell line showed supratherapeu-

Weight

20,000

tic values for both basal and stimulated conditions44 (Figure 7).
N/A

The PEC-01 cell line is known to have pancreatic progenitor

(PP) cells, which the authors conclude are responsible for
the hyperactive endocrine function. The DRC planar sheets
Islet Type

implanted in a preformed pouch also demonstrate high basal

Melligen
Porcine
islets

cells

and stimulated C-peptide levels52 (Figure 7A and B), which may

be secondary to enhanced neovascularization and engraftment
of the device, leading to faster exchange of insulin and glu-
SCID mouse
Diabetic NOD/

cose. βAir’s device using porcine islets in a nonhuman primate

model, n=3
macaques

model, 16
Model, n

also show elevated basal and stimulated C-peptide levels.64

Animal

Rhesus
Diabetic

This device contained approximately two times the number of

IEQ/kg BW as the CIT cohort, which could explain the increase
in C-peptide levels. More work is needed to understand the
consequence of supratherapeutic levels of C-peptide in large
Manufacturer,

Pharmacyte

animal and human models.

201764

201548

Essential to developing a clinically relevant BAP is using

Beta Air

enough islets to achieve physiologic insulin levels. In the CIT

Trial/

phase 3 cohort, ~11,000 IEQ/kg BW was used per patient,

y
 ADVANCES IN BIOARTIFICIAL PANCREAS 377

Figure 6. Bioartificial pancreas devices: (A) Viacyte’s PEC-encaptra device: The PEC-encaptra device is a macroencapsulating structure
that promotes neovascularization to support beta-like cells derived from hESCs. (B) Beta-Air device: The beta-air device features a central
oxygen tank with two external ports that allow refilling the oxygen chamber and venting. Multiple islet chambers are supplied by the central
oxygen tank with supplemental oxygen. (C) Nestle macro-sheets: Here, the islets are sandwiched between two layers of porous biocompat-
ible materials. hESC, human embryonic stem cells; PEC, pancreatic endocrine cell.

which resulted in 78% insulin independence at the two year preformed pouch is the only device that demonstrated appro-
mark.73 We compared devices based on IEQ/kg BW implanted priate glucose-insulin kinetics.52 The glucose stimulation curve
and found that as the number of IEQ/kg BW is increased there matched the mouse control and the C-peptide levels correlated
is diminishing return in C-peptide expression (Figure 7). There with C-peptide levels from people with type 1 diabetics who
is tremendous variability in IEQ or IPCs per kg BW implanted were cured by CIT. The data demonstrates it is possible to de-
between BAP devices, ranging between 1,200–6 × 108 IEQ or velop a BAP with near normal insulin-glucose kinetics in a
IPCs per kg BW. There is a linear increase in C-peptide ex- mouse model. Interestingly, when the DRC BAP was implanted
pression with increasing IEQ/kg BW up to 20,000 IEQ/kg BW, in a preformed pouch, the device had increased glucose-insu-
above which there is no further increase in C-peptide secretion lin kinetics; the peak blood glucose level was not significantly
as IEQ/kg BW is increased. This trend suggests there is an op- different from other DRC studies, but the time to return to
timal dose of IEQ/kg BW, above which a plateau is reached normal blood glucose levels was faster than the control mouse.
and increasing numbers of islets are superfluous. Additionally, C-peptide levels were significantly higher than
To understand the maturation of stem cell–derived IPCs, we the other DRC devices and the CIT cohort (Figure 9B).
evaluated their C-peptide secretion over time (Figure 8). Stem In contrast, no device implanted in large animal models
cell–derived IPCs do not begin to function until eight weeks achieved a normal glucose response curve compared with the
after engraftment,44 a finding which has been corroborated by normal pig control8,53,64,72,74 (Figure 9A). The most significant
multiple groups.42,46,76 After eight weeks, the IPCs continue to derangement to the glucose response curve is delayed return
develop increasing basal and stimulated C-peptide expression to euglycemia from peak glucose levels. One potential expla-
over time. It is unclear at what point the endocrine function nation is that bioartificial pancreas devices implanted in the
ceases to increase. subcutaneous space are poorly vascularized and reuptake of
A bioartificial pancreas device must secrete physiologic insulin into the blood stream is delayed. The DRC study using
levels of insulin and respond to glucose stimulation appro- planar macrosheets implanted in preformed vascularized
priately.77 To evaluate the glucose-insulin kinetics between pouches supports this conclusion, as this device demonstrated
BAP devices, we compared glucose and C-peptide stimula- faster glucose-insulin kinetics than the control. There is a pau-
tion curves (Figure 9). The DRC planar macrosheet without a city of large animal C-peptide response curve data, but the
378 PHOTIADIS ET AL.

Figure 7. Comparative function of multiple bioartificial pancreas devices in preclinical or clinical trials. A physiologic comparator is indi-
cated by clinical islet transplantation (CIT, black circle, a. and b.) and allogenic human islets (black circle, b. and c.). (A) Basal C-peptide level
(ng/mL) versus IEQ/kg body weight by device type. (B) Peak stimulated C-peptide level (ng/mL) versus IEQ/kg body weight by device type.
(C) Basal C-peptide level (ng/mL) versus IEQ/kg body weight by indwelling cell type. (D) Peak stimulated C-peptide level (ng/mL) versus IEQ/
kg body weight by indwelling cell type. The point denoted by *signifies the PEC-01 cell line, **signifies the iPSC-derived IPCs implanted in the
preformed pouch, and ***signifies the ESC-derived RA cell line.

C-peptide response curve obtained for the nonhuman primate From the analysis of the most recent BAP studies, we identi-
(NHP) model with the beta-air device is abnormal (Figure 9B). fied areas that require more research to understand their im-
Beta air does report stimulated C-peptide levels from one pact on developing a functional and durable BAP. The optimal
human patient, but these levels are subtherapeutic and did not IEQ/kg BW needs to be established for a BAP device. As ESC
result in control of circulating blood glucose. and iPSC-derived IPC’s become increasingly attractive as re-
newable islet sources, we need to establish the tumorigenic
potential of stem cell–derived IPCs and how to regulate the
maturation of an implanted stem cell BAP to achieve an op-
timal insulin-producing cell mass. Additionally, while sub-
therapeutic levels of C-peptide are clearly undesirable, more
work is needed to understand the potential deleterious effects
of supratherapeutic levels of C-peptide. Variables effecting the
glucose-insulin kinetics of devices, specifically the downward
slope of the glucose response curve, need to be determined.

Conclusion
The ideal bioartificial pancreas is easily implanted, retrieved,
protects islets without the need for immunosuppression, and pro-
vides long-term pancreatic function. A variety of techniques have
Figure 8. Time-dependent C-peptide release in stem cell-derived
islets: Average C-peptide levels produced by implanted stem cell– been used to encapsulate islets and implantation has been tested
derived islet-like cells over time, demonstrating a significant average in multiple locations. Consistent limitations with all devices are
concentration of C-peptide level starting at eight weeks postimplan- poor long-term islet viability and functionality. The reasons for de-
tation, and increasing with time up to the maximum study duration vice failure include hypoxemia, failures in diffusion, inflammatory
of 16 weeks. VC-01 represents the PEC-01 cell line, having gone
infiltration of devices, and deranged cell signaling. Although mul-
through four differentiation stages. The IC cell line is the PEC-01 cell
line brought through differentiation stages 5–7. The RA cell line is tiple groups are addressing the challenges with oxygenation and
the IC cell line depleted of pancreatic progenitors. proximity to the bloodstream, more work is needed to understand
 ADVANCES IN BIOARTIFICIAL PANCREAS 379

Figure 9. Device function in response to glucose stimulation. DRC 5M represents the Nestle macrosheet device with 1.2 × 108 IEQ/kg
body weight. DRC 15M represents the Nestle macrosheet device with 6 × 108 IEQ/kg body weight. DRC P represents the Nestle macrosheet
implanted in a preformed pouch. (A) Plasma glucose levels (mg/dL) over 120 min after glucose bolus (B) corresponding plasma C-peptide
levels (ng/mL).

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