Wearable and implantable pancreas substitutes

REVIEW

Wearable and implantable pancreas substitutes

Leonardo Ricotti • Tareq Assaf • Paolo Dario •

Arianna Menciassi

Received: 8 March 2012 / Accepted: 27 August 2012

� The Japanese Society for Artificial Organs 2012

Abstract A lifelong-implanted and completely auto-

mated artificial or bioartificial pancreas (BAP) is the holy

grail for type 1 diabetes treatment, and could be a definitive

solution even for other severe pathologies, such as pan-

creatitis and pancreas cancer. Technology has made several

important steps forward in the last years, providing new

hope for the realization of such devices, whose feasibility

is strictly connected to advances in glucose sensor tech-

nology, subcutaneous and intraperitoneal insulin pump

development, the design of closed-loop control algorithms

for mechatronic pancreases, as well as cell and tissue

engineering and cell encapsulation for biohybrid pancre-

ases. Furthermore, smart integration of the mentioned

components and biocompatibility issues must be addressed,

bearing in mind that, for mechatronic pancreases, it is most

important to consider how to recharge implanted batteries

and refill implanted insulin reservoirs without requiring

periodic surgical interventions. This review describes

recent advancements in technologies and concepts related

to artificial and bioartificial pancreases, and assesses how

far we are from a lifelong-implanted and self-working

pancreas substitute that can fully restore the quality of life

of a diabetic (or other type of) patient.

Keywords Artificial pancreas � Bioartificial pancreas �Artificial organs � Diabetes management � Pancreas

substitutes

Introduction

Type 1 diabetes (T1D) is one of the fastest growing diseases

globally [1]. It is mainly caused by a loss of functionality of

pancreatic b cells, resulting in a lack of insulin production.

Recent technological advances have led to a paradigmatic

shift in diabetes treatment, involving the introduction of

automatic and semi-automatic systems to replace traditional

procedures, and relying solely on multiple daily insulin

injections. In particular, the dream of achieving a lifelong-

implanted fully automated artificial or bioartificial pancreas

(BAP) that can fully replace the functionality of the endo-

crine pancreas represents the holy grail for T1D treatment

[2]. Indeed, such a device could also represent a solution for

other severe pancreas-related pathologies, such as pancrea-

titis and pancreas cancer, but it necessarily entails formida-

ble interdisciplinary efforts, as it involves engineering,

biological, physical, and medical issues.

The desire and demand for an automated artificial pan-

creas (AP) was generated by the discovery of insulin in

1921, but only around 1980 did the first commercial insulin

pumps appear on the market [3]. Artificial automated

devices for controlling glucose levels started to appear on

the market and evolved with the discovery and application

of novel technologies that could be utilized in their com-

ponents—insulin pumps, glucose sensors, and control

algorithms. These elements are the three pieces of the

L. Ricotti (&) � P. Dario � A. Menciassi (&)

The Biorobotics Institute, Scuola Superiore Sant’Anna,

Viale Rinaldo Piaggio 34, 56025 Pontedera (Pisa), Italy

e-mail: [email protected]

A. Menciassi

e-mail: [email protected]

T. Assaf � P. Dario

Center for Micro-BioRobotics@SSSA, Italian Institute

of Technology, Pontedera (Pisa), Italy

T. Assaf

Bristol Robotics Laboratory, University of Bristol,

Avon, Bristol BS34 8QZ, UK

123

J Artif Organs

DOI 10.1007/s10047-012-0660-6

mechatronic puzzle constituting the basis of a completely

artificial pancreas, the development of which is strictly

related to future advances in micro- and nanotechnologies.

In parallel, the idea of replacing the lost physiological

activity of b cells by directly replacing a living organ or a

portion of it has been around since 1966, when the first

pancreas transplantation was performed [4]. Great advan-

ces in the field of living cell- and tissue-based artificial

pancreas will strongly depend on new discoveries in the

fields of biomaterials, tissue engineering, and stem cell

technology. These will allow us to resolve the various

problems currently associated with the bioartificial

approach, with the aim of achieving a safe, long-term, and

effective pancreas substitute.

The following sections will highlight the current status of

scientific research concerning the artificial pancreas and

BAP platforms developed and tested so far, along with the

results achieved and the drawbacks related to each solution.

Furthermore, recent ideas and future perspectives on the

two mentioned strategies will be analyzed and discussed.

The present review aims to provide the reader with a wide-

ranging (but at the same time concise and clear) view of the

significant number of systems, technologies, and approa-

ches that are currently used to replace the functions of the

pancreas. In comparison with other recent review articles on

this topic, which normally focus on specific issues (e.g.,

pancreas or islet transplantation, glucose sensor technolo-

gies, insulin pump development, implantable artificial sys-

tems, etc.), our work aims to report and compare the main

advantages and drawbacks of all existing strategies based

on completely artificial components as well as cell- or tis-

sue-based bioartificial devices. This will allow researchers

in the field of artificial pancreases or BAPs to identify the

strong and weak points of each strategy, facilitating an

integrated vision of the problem that overcomes current

limitations through a multitechnological approach.

Insulin delivery

Insulin delivery is the first function that must be provided

by an AP. Insulin pumps, if inserted in a proper closed-loop

system, allow automatic insulin delivery when the patient’s

blood glucose level increases. Such delivery can be per-

formed according to three possible approaches: an intra-

venous route, subcutaneous insulin infusion (SCII), or

intraperitoneal insulin delivery (Fig. 1a).

History

The intravenous route was explored using implantable

insulin delivery devices from the 1970s up to the early

1990s [5], and good results were obtained in terms of the

restoration of near-normoglycemia, although some limita-

tions were also noted, which were mainly due to catheter

complications and blood clotting. This problem hindered

the further development of this route, such that other

methods became more favorable. SCII was introduced in

the late 1990s and is currently often used in insulin pump

therapy, even though it has many effectiveness and safety

issues due to delays in insulin absorption and action and

subcutaneously inserted catheter instability [6]. It has been

demonstrated that intraperitoneal insulin delivery allows

for more physiological plasma insulin profiles and more

stable implants, resulting in a dramatic reduction in severe

hypoglycemic events [7, 8].

Current trends

Current commercial pumps for subcutaneous insulin delivery

are small portable devices, and can even allow wireless

control of glycemic parameters. Examples are the IR 1200�,

OneTouch�, and Ping� insulin pumps from Animas Corpo-

ration [9], and the MiniMed Paradigm� REAL-Time Revel

System produced by Medtronic [10]. Implantable intraperi-

toneal insulin pumps are presently provided with a refillable

insulin reservoir. Refilling is a rather simple procedure that

involves inserting a syringe through the skin (by means of a

properly placed catheter) and delivering insulin into the

implanted device. An example is the Minimed 2007�

implantable insulin pump system from Medtronic.

Unsolved problems

As previously mentioned, the key issue with subcutaneous

insulin delivery remains the delay in action caused by the

time needed for subcutaneous absorption, resulting in late

insulin peaks that occur up to 120 min after the injection of

a subcutaneous bolus of regular insulin [11].

Concerning the intraperitoneal approach, the main lim-

itations are related to the high costs associated with this

technology, as well as surgical issues concerning intra-

peritoneal pump implantation and periodic substitution.

The clinical use of implantable programmable insulin

pumps has thus been limited, and there have even been

insulin aggregation issues [12] and increased production of

anti-insulin antibodies in some patients [13, 14] that have

impaired insulin action.

Future perspectives

Less invasive and cheaper implantable pumps for intra-

peritoneal insulin delivery have recently started to appear

on the market (e.g., DiaPort, Roche Diagnostics).

Mechanical insulin pumps have evolved in the last few

years, but alternative approaches have been investigated in

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parallel. New products based on polymeric smart materials

(such as gels, semi-permeable membranes and nanoporous

materials, hydrogels combined with dextran and polylac-

tide to finely control the insulin release profile, etc.) are

promising [15–17], but they do not guarantee adequate

performance and safety to allow their use in commercial

products at present. However, the development of bio-

compatible smart-materials-based novel insulin pumps

could lead to a dramatic improvement in pump function-

ality and long-term stability in the near future.

Fig. 1 a Insulin delivery systems: from the first prototypes (leftpictures: Biostator and NTG-11A systems) to modern subcutaneous

insulin infusion (central picture: OneTouch� system, from Animas)

and intraperitoneal insulin pumps (right picture: MiniMed system,

from Medtronic). b Glucose monitoring systems. Enzyme-based

sensing mechanism (left picture): once the glucose passes through the

membrane, it is oxidized by the enzyme glucose oxidase. Reduced

glucose oxidase can then be oxidized by reacting with molecular

oxygen, forming hydrogen peroxide as a by-product. At the electrode

surface, hydrogen peroxide is oxidized to water, generating a current

which can be measured and correlated to the glucose concentration

outside the membrane. Subcutaneous CGM device (central picture):

continuous glucose monitoring system from MiniMed (Medtronic).

Intravenous CGM device (right picture): Long Term Sensor System�

(LTSS) from MiniMed (Medtronic)—an electrochemical sensor with

an oxygen-based enzyme electrode that is inserted through the

subclavian vein and positioned in the superior vena cava [33].

c Control algorithms. Traditional proportional-integral-derivative

(PID) approach (left picture) and model predictive control (MPC)

algorithms (right picture). A PID controller calculates an ‘‘error

value’’ as the difference between a measured process variable and a

desired set-point, and attempts to minimize the error by adjusting the

process control inputs. On the other hand, an MPC controller utilizes

a dynamic process model to represent the behavior of a complex

dynamical system (which is hard to control using a PID algorithm)

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Glucose sensing

The second function of an AP is glucose measurement

(Fig. 1b). Many studies are currently focusing on contin-

uous glucose monitoring (CGM) and the development of

long-term-implantable subcutaneous, blood-stream, or

other kinds of glucose sensors. Such efforts are justified, as

glucose measurement is a key aspect of a closed-loop AP—

possibly the most challenging one.

History

Following the proposal, in 1967, of the first miniature

electrical transducer of glucose that could be implanted

into animals to monitor subcutaneous interstitial fluid

glucose continuously and remotely [18], electrochemical

biosensor-based glucose sensing evolved until the first

commercial CGM system, namely the CGMS�, was

developed by MiniMed [19, 20].

Concerning subcutaneously implantable sensors, despite

the fact that a considerable amount of technical effort has

been focused on this area, the good results obtained in in

vitro tests have not been replicated in vivo. In fact, after

implantation, the sensors exhibit a progressive loss of

function due to tissue reactions to the implanted device;

improvements in in vivo performance will be possible only

after a better understanding of the processes involved in

sensor inactivation has been gained [21].

Concerning glucose sensors placed directly in the blood

stream, chronic intravascular application of such sensors in

dogs revealed that they were stable for 7–108 days, and

that biocompatibility, enzyme lifetime, O2 availability, and

biochemical interference did not present a problem. Fur-

thermore, there was no need for recalibration during the

entire period of implantation [22]. This study highlighted

the potential for the longer-term application of this tech-

nology, thus suggesting its possible application in humans

by introducing a catheter-like sensor into the vena cava,

which would be retrieved and replaced every three months

in a nonsurgical procedure [23].

Current trends

Recently, some commercial sensors have been produced

by different companies and approved by the Food and Drug

Administration (FDA). These sensors include the Guardian�,

Guardian RT�, REAL-Time�, STS�, SEVEN PLUS�, and

FreeStyle Navigator�, whose accuracy was demonstrated in

several studies [24]. Developing a glucose sensor that is

designed to be implanted in the human body for long periods

may be the main challenge associated with the development

of a fully automated artificial pancreas, and current systems

are still quite far from achieving this goal.

Unsolved problems

Subcutaneously implanted sensors have inherent limita-

tions, as they measure the glucose concentration in inter-

stitium rather than blood. During rapidly changing

conditions (e.g., after a meal or during a hypoglycemic

episode), interstitial glucose and blood glucose can be

markedly different [25–27]. Therefore, CGM subcutaneous

devices require periodic calibration using multiple daily

blood glucose samples. Such calibration influences the

accuracy of CGM [28]. Clinical data acquired by Zucchini

et al. [29] recently highlighted that SCII is much more

effective than therapy based on sensor-augmented multiple

daily injections, although SCII does have some drawbacks

(e.g., mild hypoglycemic episodes can occur). In general,

despite such limitations, the current accuracy of subcuta-

neous CGM devices is considered adequate for AP closed-

loop control. In fact, this kind of sensor recently showed

only short physiological time lags (*3.28 min) in blood

glucose level detection during in silico trials [30], while

clinical trials revealed good accuracy when compared with

gold standard laboratory measurements [31]. However,

further advances in subcutaneous glucose sensor technol-

ogy (as well as in control algorithms) are needed before

they can be safely used for closed-loop glycemic control.

Since the concept of a glucose sensor that is directly

placed in the blood stream was first introduced by Gough

and Armour in 1995, no dramatic advances in this kind of

glucose sensor have occurred: intravenous blood glucose

recording is not yet the gold standard or the most useful

approach for controlling insulin pumps. This is mainly due

to concerns over patient safety due to the possibility of clot

formation or vascular wall damage [32, 33].

Future perspectives

Despite their inherent limitations, CGM devices produce

rich data sets with frequent sampling (e.g., every

5–10 min), allowing them to serve as AP-enabling tech-

nology. Future CGM devices will display to patients their

rate of change in blood glucose in real time, alerting them

to potential upcoming episodes of hypo- or hyperglycemia.

Furthermore, technological advances and the use of micro-

and nanostructured functionalized smart materials will

lead to improvements in glucose sensor lifetime and

performances.

Closed-loop control

The third componentthat is needed by an AP is an auto-

mated control unit that uses algorithms which acquire

sensor input and generate treatment outputs (Fig. 1c). An

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important aspect to consider is that an ‘‘automated’’ closed-

loop pancreas cannot approach the complexity of the native

human endocrine pancreas, which continuously takes data

from substrates, hormones, paracrine compounds, and

autonomic neural inputs and secretes hormones in

response. However, the perspectives for blood glucose

control in T1D patients have improved considerably in the

last few years.

Treatments based on multiple daily injections or con-

tinuous insulin infusion based on an open-loop approach

are associated with short- and long-term risks, as their

tendency to produce abnormally high or low glucose levels

is quite high. These approaches require human intervention

and a precise knowledge of the patient’s lifestyle (meals,

sport plans, etc.). The substantial advantage of closed-loop

control in the treatment of T1D is the opportunity to

decouple the treatment (which becomes automated) from

the patient’s daily life, but it also helps to reduce severe

complications, such as retinopathies, cardiovascular prob-

lems, and kidney failure. A purely closed-loop control

scheme determines whether to instantaneously deliver

insulin on the basis of CGM signal alone, but its use can

result in delays to the action of insulin on plasma glucose,

implying that corrections to the desired glucose levels may

arrive too late to prevent hyper- or hypoglycemic episodes.

History

It has been pointed out that a trade-off between nocturnal

regulation based on mild control actions and postprandial

regulation, characterized by prompt and energetic correc-

tion, must be achieved [34]. This can be done by means of

a closed-loop glucose control scheme combining feedfor-

ward and feedback actions [35], thus allowing prompt

compensation for meals (through the feedforward bolus) to

be coupled with the robustness of closed-loop control that

can adapt to unpredicted events, disturbances, and changes

in the patient’s dynamics. The deployment of a controller,

especially a closed-loop one, relies heavily on mathemat-

ical models. It is therefore clear that proper models of

glucose and insulin dynamics, as well as models that can be

used to predict near-future metabolic behavior, are man-

datory. Minimal models (describing the key components of

system functionality) and maximal models (nonlinear,

high-order models that provide a comprehensive descrip-

tion of metabolic regulation and include a large number of

parameters) have been well reviewed by Cobelli et al. [36],

who also described how to apply them in the most common

control strategies for AP development. Control algorithms

for AP applications have been also reviewed in [37–39].

Proportional-integral-derivative (PID) algorithms that are

used in industrial settings have also been used for closed-

loop controls. It has also been argued that the pancreatic

islets are actually controlled by proportional, derivative,

and integral factors [40]. While the PID approach is rela-

tively straightforward, and is able to mimic many typical

islet response phases using its three components, system

optimization is often difficult, with manual tuning required.

A drastically different approach is implemented by

model predictive control (MPC) algorithms, which rely on

the use of an internal model to predict future outcomes

based on past and current states and a mathematical model

called cost function minimization. This approach makes it

possible to find a sequence of control inputs that will lead

to the desired future outcomes.

Current trends

Many modern MPC algorithms are based on the minimal

model of glucose Kinetics, developed by Bergman et al.

[41] in 1979, and they represent a good solution for the

principal AP control dilemma: finding a trade-off between

slow-paced regulation, which is well suited to mild control

actions that can be applied to a quasi-steady state (e.g.,

overnight), and postprandial regulation, which calls for

prompt and energetic correction [42].

MPC has shown to be suitable for multivariate nonlinear

systems such as the human body, and it gives demonstrably

better performances than PID control with patient-specific

fine-tuned gains [43]. Nonlinear model predictive control

(NMPC) or linear model predictive control (LMPC) algo-

rithms can be used, and several successful clinical trials

using MPC were recently published [44–47]. MPC also

allows individualization using patient-specific parameters

[48].

Unsolved problems

The PID approach has inherent limitations due to

unavoidable time lags in glucose sensing (especially via the

subcutaneous route) and insulin action.

MPC algorithms are promising tools, but they face addi-

tional difficulties. One is inter- and intrapatient variability.

Fortunately, MPC algorithms can be ‘‘personalized’’ using

patient-specific model parameters. Another challenge is the

need to provide the algorithm with certain feedforward

capabilities—the ability to use a combination of feedforward

(e.g., patient-initiated) and feedback (controller-initiated)

insulin delivery—to address the dilemma of finding a suit-

able trade-off between slow-paced regulation in a quasi-

steady state and prompt correction for meals.

Future perspectives

Advanced MPC algorithms represent a promising solution

for closed-loop APs, above all due to the ability to set their

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parameters in a patient-specific manner, thus overcoming

the issue of patient variability. Novel technologies are also

emerging, such as fuzzy logic algorithms and advanced

neural networks, which could foster the development of

effective and safe fully automated APs.

Totally artificial implantable pancreas

History

The first attempt to build an automated device to control

human blood glucose dates back to 1964: the concept was

based on continuous blood glucose sensing and delivering

insulin through a servomotor, as controlled by an ‘‘on–off’’

algorithm [49]. Obviously, such an approach was too

simplistic to provide good glycemic control, but this study

established many of the technical methods used by artificial

pancreas developers during the subsequent decade.

After this pioneering study, researchers continued to

tackle the technological challenge of creating an artificial

pancreas substitute, and good results were achieved around

1980 with the development of the Biostator (Ames Divi-

sion, Miles Laboratories, Elkhart, IN, USA), a device

combining a glucose oxidase membrane-based sensor for

CGM and a simple proportional-derivative algorithm to

control intravenous insulin delivery [50, 51]. The Biostator

was far from being an implantable device due to its bulk-

iness, limitations of the control algorithm, as well as a

problem with pump-induced insulin aggregation. STG-11A

and STG 22 (Nikkiso, Tokyo, Japan) were two bedside-

type commercial APs developed in the same period. These

consisted of an extracorporeal intravenous glucose sensor

with a blood-sampling double-lumen catheter, a propor-

tional-derivative control algorithm, and an intravenous

insulin and glucose delivery system. These devices were

used by Hoshino et al. [52, 53], who placed the glucose

sensor in the superior vena cavae of acutely ill severe

patients with glucose intolerance. However, the bulkiness

of these devices did not allow a normal lifestyle, as the

patient was obliged to lay in bed in order to monitor his/her

glycemia. Over the following 30 years, insulin pumps and

glucose sensors became smaller and more portable, thus

bringing such devices closer to the ideal of wearable or

implanted APs [54–60] (Table 1).

Current trends

Wearable systems have evolved considerably over the last

decade, and many commercial devices have been pro-

duced. In the framework of the project ADICOL

(ADvanced Insulin infusion using a COntrol Loop), funded

by the European Commission from 2000 to 2003, a wear-

able AP was developed which combined a microdialysis

system for sampling interstitial fluid (open flow microp-

erfusion) with an enzymatic sensor for measuring the fluid

glucose concentration and a closed-loop SCII, controlled

by an MPC algorithm [61, 62]. During 2008 and 2009, the

first multinational study comparing the use of a closed-loop

control artificial pancreas to state-of-the-art open-loop

therapy in adult T1D patients was completed [63]. A sub-

cutaneous glucose sensor (Freestyle Navigator�) detected

glycemia and sent the data to an MPC algorithm, actuating

a subcutaneous insulin pump (Deltec Cozmo). The trials

suggested that closed-loop delivery of insulin improved

overnight control of glucose levels and reduced the risk of

nocturnal hypoglycemia in comparison with traditional

insulin pump therapy. More recently, Bruttomesso et al.

[64] combined subcutaneous glucose sensing and contin-

uous SCII, as contolled with an MPC algorithm, for the

treatment of T1D patients in both Padova and Montpellier.

In particular, a Freestyle Navigator� CGM system and an

Omnipad� insulin pump were applied in each trial, and

resulted in good control of glycemia in the tested patients.

The safety and efficacy of overnight closed-loop insulin

delivery in comparison with traditional ‘‘open-loop’’ insu-

lin pump therapy in adult T1D patients was also demon-

strated by Hovorka et al. [65] in 2011, using again a

Freestyle Navigator� glucose sensor and a Deltec Cozmo

insulin pump.

Table 1 Representative artificial pancreas systems and their characteristics

Artificial pancreas type Glucose sensing method Control algorithm Insulin delivery system Tested on References

Bedside Intravenous PD Intravenous Humans [50–53]

Wearable Interstitial MPC Subcutaneous Humans [61, 62]

Wearable Subcutaneous MPC Subcutaneous Humans [63–65]

Partially implanted Intravenous MPC Subcutaneous Pigs [67]

Partially implanted Intravenous MPC Subcutaneous Humans [68]

Partially implanted Subcutaneous PID Intraperitoneal Humans [69]

Totally implanted Intravenous PD Intraperitoneal Humans [66]

AP artificial pancreas, PD proportional-derivative control, PID proportional-integral-derivative control, MPC model predictive control

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Implanted AP development would surely represent a

more challenging approach. Renard et al. [66] reported the

results obtained with a closed-loop system called the Long

Term Sensor System�, consisting of an intravenous long-

term enzymatic sensor, an implantable insulin pump

delivering insulin into the peritoneum, and a controller

with a PD algorithm. There was no harmful complication

related to the implants for an average duration of nine

months, and this remains the only closed-loop system to

utilize intravenous sensing and intraperitoneal insulin

delivery to date. Although this study demonstrated the

feasibility of a fully implantable AP, it also highlighted the

need to improve sensor structure, increase longevity, and

decrease sensor delay, effecting closed-loop control at meal

times. A bihormonal closed-loop system for glucose con-

trol was tested in 2009 by El-Khatib et al. [67] on thirteen

diabetic pigs. Blood glucose was sampled through an

implanted sensor in the vena cava, while insulin and glu-

cagon were provided subcutaneously by means of a 6 mm

cannula (Quick-set, Minimed Medtronic), and a generalized

predictive control (GPC) algorithm was implemented. The

study revealed the feasibility of bihormonal closed-loop

glycemic regulation using an implanted glucose detection

unit. The same group performed a similar study in humans

in 2010, using an intravenous blood glucose monitoring

system, a subcutaneous insulin and glucagon pump, and a

customized MPC algorithm [68], obtaining good results in

glycemic regulation. A subcutaneous glucose sensor and an

intraperitoneal insulin pump were used by Renard et al. [69]

in 2010 to test a new partially implanted AP model. This

approach developed from the observation that subcutaneous

insulin delivery from a portable pump guided by a subcu-

taneous glucose sensor encountered delays and variability

in insulin absorption. An implanted pump was therefore

tested (MMT-2007D, Medtronic) on eight adult T1D

patients for at least three months; the pump was controlled

by a PID algorithm receiving glycemic data from a subcu-

taneous glucose sensor (CGMS�, Medtronic). Results

demonstrated the feasibility of such an approach, and

encouraged further studies.

Unsolved problems

Together with other factors, the limited success of present

closed-loop wearable artificial pancreases is related to

psychological aspects, which have been demonstrated to be

a key issue in therapy success [70]. The present paradigm

for closed-loop artificial pancreases is based on glycemia

detection by means of subcutaneous glucose sensors and

insulin delivery by means of subcutaneous insulin pumps.

This implies the need for portable external devices, as well

as periodic replacement of catheters. A T1D patient is

therefore obliged to constantly pay attention to such

devices, avoiding certain daily life behaviors or modifying

them (sporting activity, showers, etc.). Furthermore, car-

rying devices (or transcutaneous gate accesses) on the body

can lead to body image issues, causing negative feelings of

shame and embarrassment (an especially important factor

in children and adolescents [71]). This goes against the aim

of an artificial pancreas—to fully replace the lost pancre-

atic functionality, allowing the patient to forget his/her

pathology and thus to fully restore their quality of life.

The main obstacle to the development of a working and

safe implantable AP is the current status of glucose sensors,

which are insufficiently accurate and cannot ensure long-

term stability. Furthermore, the following three main

complex implantability-related problems need to be

addressed: recharging the battery of the implanted device,

long-term insulin stability in the implanted reservoir, and

refilling the implanted insulin reservoir without the need

for periodic surgical interventions and possibly without

transcutaneous implanted gate accesses.

Infection-related issues

Modern medicine often takes advantage of an increasing

number of implantable medical devices, but their benefits

can be attenuated by the morbidity, mortality, and expense

associated with implant-derived infections. The presence of

foreign bodies in patients lowers their threshold to bacterial

infection and generates local immunosuppression. Oppor-

tunistic microorganisms can thus exploit this weakening in

the patient’s defenses. Furthermore, bacteria initially

adsorb onto the implant surface, often forming an adherent

biofilm that exhibits increased protection from host

defenses and enhanced resistance to antibiotic treatments

[72, 73]. Invasive medical implants, when infected, can

actually result in resistant chronic infections or tissue

necrosis. The design and development of a long-term-

implantable artificial pancreas must face these issues and

provide approaches that reduce or eliminate infections of

the implanted device.

Much research effort is currently focused on developing

strategies to prevent biofilm formation, including physio-

chemical modification of the biomaterial surface to create

antiadhesive surfaces, the incorporation of antimicrobial

agents into medical device polymers, mechanical design

alternatives, and the release of antibiotics. Biosurfactants

have also been reported to be a promising strategy, as they

effectively inhibit bacterial adhesion and retard biofilm

formation. Important recent reviews on this topic can be

found in [74, 75].

Bloom et al. reported interesting results concerning the

implantation of electronic devices using an antibacterial

envelope. This system was a polymer mesh that was able to

release two antibiotics (minocycline and rifampin) after

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implantation, thus reducing the risk of infection [76]. The

use of protective envelopes in this manner could even be a

good solution for the implantation of an artificial pancreas,

but the device itself could be built from functionalized

materials that are able to release antimicrobial agents in a

controlled way, as suggested in recent literature [77–79].

Xu and Siedlecki [80] also suggested that certain nano-

structured surfaces can prevent bacterial adhesion, so

introducing patterned surface texturing could provide an

effective means to reduce biofilm formation and implant-

associated infections.

In the future, it is hoped, the sensitivity and accuracy of

new emerging methods such as those based on mass

spectroscopy [PCR-electrospray ionization (Ibis) and

matrix-assisted laser desorption ionization coupled with

time-of-flight analysis (MALDI-TOF)] for the diagnosis of

bacterial infections will be demonstrated in depth. These

improvements in diagnosis should be coupled with

advanced control strategies: anti-infective or infection-

resistant materials, biofilm agent disaggregation, comple-

mentary therapies, vaccines, and other preventive measures

resulting from progress in our knowledge of pathogenesis

and molecular epidemiology, which could revolutionize the

treatment of implant infections [81].

Future perspectives

Progress in AP development is expected to rely partly on

the outpatient setting. This step would require specific

elements, such as a server and communication tools for

remote monitoring as well as remote intervention. How-

ever, the dream is to achieve a fully automated closed-loop

long-term artificial system that is able to fully (i.e., no loss

of quality) replace endocrine pancreatic functionality for

the entire remaining lifetime of the patient. This ambitious

objective may be feasible in the not-so-distant future due to

novel and emerging technologies (micro- and nanotech-

nologies, novel biomaterials, miniaturized sensors and

actuators, etc.) that, if combined appropriately, would

allow the development of APs with unprecedented

performance.

The biohybrid approach

History

The path for research into pancreatic islet transplantation

was paved by the discovery of a collagenase-based method

of isolating islets [82], while the first examples of islet

transplantation—which made it possible to reverse diabetes

in rodents and primates—appeared in 1973 and 1975,

respectively [83, 84].

In 2001, a ground-breaking paper on human islet allo-

transplantation was published, describing the use of a novel

immunosuppressive regimen together with improved islet

isolation methods [85]. This technique yielded excellent

results and became the preferred islet transplantation

method for diabetic patients.

A smart alternative to transplantation procedures is

represented by bioartificial organs, which contain cells or

cell clusters within a synthetic biocompatible semiperme-

able membrane, thus separating the foreign tissue from the

host’s immune system [86, 87]. BAPs fully mimic the

behavior and function of a healthy pancreas, eliminating

the need for immunosuppressing drugs. The biocompatible

membrane allows the viability and functionality of cells to

be retained by providing them with access to nutrients,

oxygen, and stimulatory agents, while it also prevents

immune cells and antibodies (which have relatively high

molecular weights) from crossing the membrane. This can

be achieved by tailoring the membrane pore size appro-

priately. Several different BAP models have been studied

over the last few decades, but to be accepted as an alter-

native therapy a model must be biocompatible, its mem-

brane must exhibit good diffusional properties, the device

must be easy to retrieve or biodegradable, and it must be

able to maintain cell viability and functionality for long

periods of time. An extensive review of biocompatible

materials used in BAP devices is provided by [88].

An overview of BAP classification is shown in Fig. 2.

Devices are mainly divided into two groups: intravascular

and extravascular devices. Intravascular devices are usually

made of hollow fiber membranes, and are blood perfusion

systems, inserted as an artery-to-vein shunt in the reci-

pient’s body [89]. Significant results were obtained by

Monaco et al., who used a device consisting of two con-

centric tubular membranes with one end anastomosed to an

artery and the other to a vein. The blood was allowed to

perfuse the lumen of the inner membrane, allowing the

transport of oxygen, nutrients, and signaling molecules to

the cells, which were placed in the annular space between

the two membranes [90]. Other similar devices were

transplanted in vivo into dogs [91, 92], and ex vivo into

monkeys [93, 94]. While the ex vivo implants showed good

functionality for several months, in vivo grafts never lasted

more than a few days, mainly due to blood coagulation

which led to to thrombosis. More recently, Ikeda et al. [95]

developed a new intravascular BAP that showed good

blood glucose control in pancreatectomized pigs, but strong

anticoagulation treatment was still necessary.

Extravascular BAPs can be classified into macrocap-

sular and microcapsular systems. Both approaches show

some advantages when compared with their intravascular

counterparts: they lead to a smaller risk from surgical

implantation, are easier to retrieve (for macrocapsules),

J Artif Organs

123

make it possible to re-seed the device, and allow flexibility

in terms of size. However, they also show some drawbacks,

mainly related to the diffusional hindrance of the transport

of nutrients, hormones, oxygen, and metabolites. Other

major problems with extravascular implants are the fibrotic

response to the device, cellular adherence to the outer wall

of the membrane, and loss of physical integrity of the

capsule, especially for microcapsules. Flat sheet and hol-

low fiber based BAPs are macrocapsular structures that are

usually implanted in the back wall of abdominal muscle, in

the peritoneal cavity, in subcutaneous sites, etc. [96–99].

Icard and co-workers [100] studied the best implantation

site for an extravascular hollow fiber device in pig recipi-

ents, and found that the site leading to the best tissue

functionality and the lowest fibrotic response was the

peritoneal cavity.

Current trends

Macrospheres constitute another type of macrocapsular

BAP. In this approach, islets are enclosed in a relatively

large hydrogel that can be handled macroscopically and is

easy to retrieve in cases of implant failure or tumor for-

mation [101, 102]. In microencapsulation, one or a few

islets are immobilized in a structure made of alginate or

other hydrogels. Their large surface area favors substance

exchange, but these systems are difficult to retrieve once

implanted into the body, especially if cellular adherence or

fibrotic reactions occur.

DIABECELL� is a porcine insulin-producing cell that is

microencapsulated in alginate hydrogel and has already

used in clinical trials [103, 104]. It has been demonstrated

that implanting this product into the abdominal cavities of

diabetic patients produces beneficial effects, such as

reduced HbA1c levels and/or reduced insulin doses, with-

out the need for any immune suppression.

Unsolved problems

Despite advances in transplantation techniques, patients

undergoing whole-pancreas or islet transplantation must

still take immunosuppressive drugs for the rest of their

lives. Such drugs show significant toxicity and may give

rise to other complications, such as an increased risk of

infection or cancer. This therapy is also limited by the

scarcity of human donors.

The intravascular approach to BAP shows several

advantages, but its main drawback is still blood coagulation

and consequent thrombosis. Microbeads implanted into the

abdominal cavity are also promising, but they are not

retrievable, so further studies are needed to assess the long-

term safety of the implanted device. The main problems

related to the use of microcapsules in vivo remain the

development of a fibrotic response, difficulties involved in

microcapsule construction, and determining the ideal

polymer composition.

Future perspectives

The long-term safety issues connected to the use of intra-

vascular, macrocapsular, and microcapsular devices will

determine their success or failure as bioartificial devices to

replace endocrine pancreatic functionality in decades to

come. Future advancements in micro- and nanobiomaterials

will surely drive improvements in these approaches, pro-

viding new constitutive elements and new biotechnological

Fig. 2 Classification of organ/tissue replacement approaches and

bioartificial pancreas devices. There are two possible approaches to

organ/tissue transplantation (yellow arrows): whole pancreas trans-

plantation or islet transplantation. The bioartificial pancreas approach

(blue arrows) implies the use of intravascular or extravascular

devices. Among extravascular devices, macrocapsular and microcap-

sular systems are the most commonly used and studied; in turn,

macrocapsular devices can be divided into flat sheets, hollow fibers,

or macrospheres (color figure online)

J Artif Organs

123

strategies to overcome the problems of thrombosis, fibrotic

response, and other unwanted body reactions to implanted

devices. In the near future, microelectromechanical systems

(MEMS) could also be integrated into bioartificial devices to

monitor cell status (by means of miniaturized sensors) or to

interfere with cell activity (via properly designed actuators).

This could allow the potential of a mechatronic approach

within a BAP to be exploited.

Recent ideas and promising technologies

Recent advances in micro- and nanotechnologies, together

with the development of new smart materials and plat-

forms, have allowed new generations of APs, BAPs, and

components to be developed.

If we consider artificial insulin pumps, some examples

include the polymer alloy membrane-based insulin pump

proposed by Uchiyama et al. [105] and the thin film Nitinol

pumps presented by Schetky et al. [106]. Recent approa-

ches to glucose sensing are represented, for instance, by

noninvasive measurements performed using near-infrared

spectroscopy [107], the novel highly responsive needle-

type sensor proposed by Ichimori et al. [108] and based on

polyimide, and the enzyme-free sensor developed by

Yoshimi and co-workers [109] using the gate effect of a

molecularly imprinted polymer. Research is also pro-

gressing in the field of control algorithms, with the gen-

eration of novel approaches such as adaptive, fuzzy logic,

and neural network based algorithms, with the aim being to

control blood glucose through automatic self-ameliorating

methods [110–112].

Recently, a new invention proposed a new implantable

AP with a wireless battery recharging system and a

noninvasive strategy for refilling the insulin reservoir based

on swallowing polymeric capsules [113]. Figure 3 depicts

this system.

A wireless energy transfer system exploiting nonradiative

energy transfer allows the implanted battery to be recharged

by simply wearing a belt (for example, overnight), [114,

115], while the insulin reservoir is refilled by swallowing

sensorized capsules. The system requires careful consider-

ation of surgical and long-term biocompatibility issues, but

those aside, it represents an interesting trade-off in the

development of a self-working implantable AP that can

completely restore T1D patients’ quality of life.

This technology could also open novel avenues for the

treatment of critically ill patients affected by other meta-

bolic pathologies, such as impaired glucose tolerance

(IGT), type 2 diabetes, and the combination of medical

disorders known as metabolic syndrome in general. The

possibility of implanting a reliable, lifelong-implanted

organ that is able to deliver specific substances, when

needed, into the peritoneal cavity or directly into the

bloodstream would allow closed-loop continuous drug

treatment capable of countering or even preventing the

negative effects of these metabolic alterations.

Concerning BAP evolution, progress in nanotechnology

will surely encourage the development of microencapsu-

lation techniques and membrane preparation, allowing

more precise control over pore size, and nanoscale-pat-

terned surfaces that permit selective adhesion of proteins or

signaling molecules. Together with advances in biocom-

patible materials, this will lead to enhanced safety and

functionality of implanted devices. Furthermore, future

insights into iPS cell differentiation will allow researchers

to obtain pancreatic-like tissue that functions in vitro and

can be used in combination with retrievable BAPs.

Fig. 3 The implantable and refillable artificial pancreas architecture

[113]. A sensorized insulin capsule, once swallowed, reaches the

docking system at the stomach wall and docks with it. Insulin is then

transferred from the capsule to the implanted insulin reservoir. A

glucose sensor triggers the closure of the control loop with an

intraperitoneal insulin pump; an external receiver allows the status of

the implanted device to be monitored; and an external charging belt

allows wireless recharging of the implanted batteries

J Artif Organs

123

Conclusions

In the last few decades, considerable research effort has

been focused on two different approaches with the same

final aim: to restore the quality of life of diabetic patients

and, in general, of patients suffering from pancreas-related

pathologies. These two approaches are to develop a totally

artificial mechatronic wearable or implanted system or to

realize a bioartificial device containing insulin-producing

living cells. In this review, recent progress and scientific

advances in these two directions have been reported and

discussed, highlighting the advantages and drawbacks of

each strategy. The main bottleneck in the development of a

working and safe AP is represented by glucose sensors,

which are not yet sufficiently accurate and stable over the

long term to be used in APs. Furthermore, for implantable

APs, insulin stability, charging the battery of the implanted

device, and refilling the implanted insulin reservoir without

the need for periodic surgical interventions and possibly

without transcutaneous implanted gate accesses are the

other main issues to address. Also, none of the BAP

devices developed so far have managed to reduce the

associated fibrotic response to acceptable (i.e., negligible)

levels. Furthermore, diffusional limitations imposed by the

encapsulating material and the capsule size are crucial

issues to graft success. The use of new biomaterials and

new microcapsular designs have been attempted with some

degree of success, but BAPs still need considerable

improvement before they can be accepted routinely in the

clinical setting. Recent ideas in and future perspectives on

this field of research have been also described in this paper,

which has attempted to envision the directions that future

research efforts will take.

Acknowledgments The authors are deeply grateful to Professor

Claudio Cobelli, whose precious suggestions were of primary

importance during the preparation of this review article.

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