Advances in Bioscience and Biotechnology, 2012, 3, 782-787 ABB
http://dx.doi.org/10.4236/abb.2012.326098 Published Online October 2012 (http://www.SciRP.org/journal/abb/)
Prevention of beta cell death in chronic pancreatitis
Huansheng Dong, Katherine A. Morgan, David B. Adams, Hongjun Wang*
Department of Surgery, Medical University of South Carolina, Charleston, USA
Received 29 August 2012; revised 30 September 2012; accepted 6 October 2012
ABSTRACT
Chronic pancreatitis is best described as a relentless,
continuous inflammatory destruction of the pancreas
parenchyma, characterized by irreversible destruc-
tion of the exocrine tissues, fibrosis, and at the late
stage, the destruction of endocrine cells. Current
therapies for chronic pancreatitis patients focus on
pain relief by medical and minimally invasive endo-
scopic treatment as well as surgical management with
resection of diseased parenchyma and drainage of
obstructed ducts. Radical treatment of chronic pan-
creatitis has been successful with total pancreatic-
tomy and islet autotransplantation (TP-IAT) that
may prevent maladaptive intractable pain pathways
and also avoid pancreatogenic diabetes in the well-
selected patient. Distinct loss of pancreatic islet cells
occurs in about 30% - 50% of patients during the
progression of chronic pancreatitis when severe fi-
brosis develops at the late stage of the disease. Pro-
found β cell apoptosis induced by stresses encoun-
tered during islet isolation and transplantation fur-
ther compromises β cell survival and function after
TP-IAT. The molecular mechanisms that lead to β
cell dysfunction in chronic pancreatitis remain largely
undelineated. In this review, we summarize factors
that may contribute to β cell apoptosis during the
disease progress and after TP-IAT and discuss poten-
tial interventional approaches that may prevent islet
cell death during these processes. Such information is
critical to the development of therapeutic protocols
that can preserve the viability and function of β cell in
patients with chronic pancreatitis.
Keywords: Chronic Pancreatitis; Islet
Autotransplantation; Beta Cell Apoptosis; Protective
Gene
1. INTRODUCTION
Chronic pancreatitis (CP) is characterized by long-
standing inflammation of the pancreas that is notable for
the development of progressive pain, fibrosis and loss of
exocrine and endocrine function [1]. Approximately
15,000 Americans are diagnosed with chronic pancreatic-
tis each year. The pathophysiology of chronic pancreatic-
tis is dominated by acinar cell death and loss of exocrine
function of the pancreas. Endocrine insufficiency that
occurs much later in the disease can lead to type 3c dia-
betes [2,3]. Current therapies for chronic pancreatitis
patients focus on pain relief by medications and a variety
of minimally invasive endoscopic procedures as well as
surgical treatment with resection of diseased parenchyma
and drainage of obstructed ducts [3,4]. Radical treatment
of chronic pancreatitis has been successful with total
pancreatectomy and islet autotransplantation (TP-IAT)
that may prevent maladaptive intractable pain pathways
and also avoid pancreatogenic diabetes in the well-se-
lected patient [5].
Although the pathogenesis and biological behavior of
chronic pancreatitis has been widely studied, mecha-
nisms of apoptosis and proliferation of endocrine (e.g.,
acinar) and endocrine (e.g., insulin-secreting
 ) cells un-
der the conditions of chronic pancreatitis remain poorly
defined. Profound apoptosis of acinar cells are observed
in chronic pancreatitis patients, while
 cells have been
found less vulnerable than acinar cells at the early stage
of chronic pancreatitis [6,7]. Nevertheless,
 cell apop-
tosis over a prolonged period of inflammation that influ-
ences insulin secretion develops late in the disease proc-
ess. Diabetes occurs in around 30% - 50% of patients
diagnosed with long-term chronic pancreatitis [8]. In
advanced stages o f chron ic pancreatitis, reductio n of islet
cells corresponds with severe
 cell dysfunction due to
prolonged exposur e to inflammator y cytokines, oxid ative
stresses and gene dysfunction [7,9]. Moreover, non-im-
mune related stresses encountered during islet isolation
and transplantatio n also resu lts in a significant nu mber of
islets undergoing apoptosis after TP-IAT, which further
comprise the function of
 cells [10].
In this review, we summarize molecular mechanisms
that lead to
 cell dysfunction during the progress of
chronic pancreatitis and after TP-IAT and discuss inter-
ventional therapies that might improve the viability and
function of
 cells. Understanding such mechanisms will
*Corresponding author.

H. S. Dong et al. / Advances in Bioscience and Biotechnology 3 (2012) 782-787 783
not only lead us to a better understanding of the patho-
genetic mechanisms leading to
 cell death in chronic
pancreatitis, but also help develop efficient therapeutic
treatment protocols for this disease.
2. MECHANISMS OF  CELL DEATH
DURING THE PROGRESS OF
CHRONIC PANCREATITIS
Long-term inflammation in patients with chronic pan-
creatitis impairs
 cell function and as many as 30% -
50% of patients develop a type of diabetes that differs
from type 1 and type 2 diabetes [8]. The diabetes associ-
ated with chronic pancreatitis has been labeled as “type
3c” diabetes [11]. Type 3c diabetes is caused by the
apoptosis of β cells and is generally not diag nosed in the
early stages of chronic pancreatitis, but manifests itself in
a later stages of the disease irrespective of the etiology of
chronic pancreatitis [12 ].
At the early stage of chronic pancreatitis, the damage
to the pancreas is highly specific for the exocrine com-
partment and affects the endocrine islets to a less extent
[13]. For example, Fas (CD95)/Fas ligand (CD95L)-
mediated islet cell destruction by CD95L expressing cy-
totoxic T cells is an important mechanism in the devel-
opment of type 1 diabetes, but does not occur at the same
extent in chronic pancreatitis patient. Exocrine cells ex-
press CD95, and shed their death by binding to the death
ligands (CD95L) on infiltration T lymphocytes in the
presence of IFN-γ, while islet cells secured themselves
by expressing CD95L instead of CD95. Thus, T cells
infiltrates are prevalent within acinar cells but rare with in
islets in pancreas with chronic pancreatitis [13-15].
Moreover, a strong induction of TNF-related apoptosis-
inducing ligand (TRAIL) receptor 1 and 2 (TRAIL-R1
and R2) is observed in exocrine cells, while islet cells
only express TRAIL-R4 [15]. TRAIL released locally by
activated pancreatic stellate cells binds to TRAIL-R1 and
R2 specifically, but not TRAIL-4R, and selectively lead
to exocrine apoptosis [16]. In addition, islet cells have
been shown to retain their “immune-privileged” status by
activated anti-apoptotic programs through NF-B [17-
19].
As the disease progresses, chronic inflammation can
lead to β cell apoptosis and dysfunction. Chronic in-
flammation causes increasing stress and cytokine secre-
tion by both macrophages and T lymphocytes with
marked fibrosis that eventually leads to β cell apoptosis
and clinical diabetes [20]. The changes in the internal
milieu of pancreatic tissue in chronic pancreatitis arising
from the chronic inflammation and cytokine release (e.g.,
IFN-γ, TNF-α) that leads to deranged cellular crosstalk
and signaling mechanisms and altered function of islet
cells. Qualitative and quantitative changes in cytokine
signaling pathways determine the fate of β cell to live
and proliferate or to undergo apoptosis [21]. The apop-
tosis of β cell are likely caused by the cytokine expres-
sion, oxidative stress, and reduced expression of certain
genes (e.g., pancreatic duodenal homeobox 1) in the
pancreas [22-24]. Apoptosis of β cells, when it occurs,
has been ascribed to immune processes initiated by
CD8+ T cells or CD4+ T cells dependent on Fas/FasL as
well as cytokines (e.g., IFN-γ and TNF-α). Apparently,
cellular and molecular events leading to β cell apoptosis
represent the adaptive response of normal islets towards
the noxious environment caused by proinflammatory
cytokines.
3. DEATH OF  CELLS AFTER TP-IAT
TP-IAT is being increasingly investigated and used as a
treatment option for pain relief, and it is also used to
prevent pancreatogenic diabetes in chronic pancreatitis
[25]. Among all the treatment options, TP-IAT is a safe
and effective option for chronic pancreatitis patients and
has the potential to eliminate pancreatic pain without
total sacrifice of the endocrine function of the pancreas
[4,26,27]. Islets transplanted into the liver via the portal
vein were found to have improved functions with time
[28]. However, even though TP-IAT can improve quality
of life and decreased narcotic requirement, more than
60% of patients require long-term insulin treatment [4,
27,29-31]. Non-immune related stresses encountered
during islet isolation and transp lantation results in a large
number of islets undergoing apoptosis immediately after
transplantation, and as many as 50% - 60% of islet cell
apoptosis happens at 2 - 3 days post transplantation even
under optimal conditions [32,33]. The death of pancre-
atic islets are likely due to transplantation-associated
stress which include hypoxia, nutrient deprivation, reac-
tive oxygen species, pro-inflamma tory cytokines ind uced
during harvesting, isolation , and implantation of the islet
cell mass [10,34].
4. APPROACHES TO PROTECT β CELL
FROM APOPTOSIS IN CHRONIC
PANCREATITIS PATIENT
In order to prevent the chronic inflammation in chronic
pancreatitis patient, altering the environment where islets
reside may help relieve the stress and improve islet sur-
vival and function. For example, strategies such as die-
tary modification, oral hypoglycemics, and exogenous
insulin can help alleviate the stress of β cell, and thus
preserve islet fun ction (Figure 1) [35,36].
It has been postulated that patients with chronic pan-
creatitis should be considered for TP-IAT before severe
islet destruction occurs. Patient islet quality and quantity
determines β cell function after transplantation. Insulin

H. S. Dong et al. / Advances in Bioscience and Biotechnology 3 (2012) 782-787 784
Figure 1. Approach to improve islet survival and function dur-
ing chronic pancreatitis progress and during TP-IAT.
requirement is well-known to be associated with lower
islet cell yield after transplantation [25,37]. Low islet
yields are common in patients with long-term chronic
pancreatitis, as inflammation and fibrosis lead to pancre-
atic endocrine failure over time [38,39]. In the early
stages of chronic pancreatitis, islet/β-cell remains intact
morphologically and functionally and pa tients usually do
not have diabetes [17]. In contrast, the number of islet
cells were shown to be significantly reduced corre-
sponding to the stage of the disease before the onset of
diabetes [7,9]. Both the exocrine and endocrine tissues
have greater destruction in chronic pancreatitis patients
compared to patients with minimal duct disease or non-
dilated chronic pancreatitis [40]. Thus, islet transplanta-
tion early in the progression of chronic pancreatitis can
maximally preserve the endocrine function of the islets
[37].
5. APPROACHES THAT CAN IMPROVE
THE FUNCTION OF ISLETS DURING
TP-IAT
Strategies that enable β cell resistance to stresses during
TP-IAT would prevent β cell apoptosis, thereby improv-
ing clinical application of islet transplantation [4,27,29].
Several approaches are currently being explored to im-
prove islet survival after transp lantation including induc-
tion of protective genes expression ex vivo in islets dur-
ing harvest, physically isolating islets from insults using
encapsulation techniques, transplanting islets to a better
site that promote survival, and so on (Figure 1).
Induction expression of protective gene has been s h o wn
able to protect islet cells from stress-induced apoptosis
[41]. A protective gene is a gene that is upregulated in
response to stress through specific signaling cascades
and transcription factor regulation that when induced
participate in promoting cell survival [41]. Many protec-
tive genes including heme oxygenase (HO-1), A20,
B-cell lymphoma 2 (Bcl-2), Bcl-x, heat shock proteins,
biliverdin reductase (BVR), and antioxidant enzymes
have been found to be expressed in pancreatic islets, and
their induction leads to protection against apoptosis and
other injuries while their absence leads to a heightened
response to stress [41-45]. Most protective genes exert
their protection via their anti-inflammatory property and
prevention of
 cell apoptosis.
Islet encapsulation with biocompatible materials have
been shown function as an immunoisolation approach to
facilitate survival of syngeneic, allogeneic and xenoge-
neic islets for decades [47-49]. Islet encapsulation can
exert both “isolation” and “modulation” effects by physi-
cally isolating islets from complement molecules, IgG
and host immune cells while delivering cytoprotective
molecules locally to the islets to p rotect those islets from
stress-induced apoptosis. Islets from chronic pancreatitis
patients are extremely fragile due to long-term inflame-
mation in the pancreas. Therefore coating islets with
nanoparticles loaded with protective molecules may well
preserve their function after islet autotransplantatio n.
Significant progress has been made in developing
suitable materials with reliable biocompatibility, me-
chanical and chemical stability, and required permselec-
tivity for cell encapsulation [50-53]. Islet encapsulation
with microcapsules prevents them from apoptosis [52,54].
Modifying islet surfaces with bioreactive chemicals pre-
vents blood-mediated inflammatory responses [55] and
prolonged survival of islet allograft [56]. Coating islets
with FDA-approved poly(lactide-co-glycolide) (PLGA)
nanoparticles increase islet function [57,58]. PLGA has
been developed for many years and approved by the
FDA for drug delivery based on its biodegradability, drug
biocompatibility, suitable biodegradation kinetics and
mechanical properties and ease of processing [59-61].
Loading drugs into nanoparticles where drugs are only
active in the target area of the body, such as locally to
islets, can avoid toxicity and side effects when adminis-
tered systemically [62].
In addition, transplanting islets into other sites less
stressful may promote their survival. Currently islets are
transplanted into the liver of patient via portal vein infu-
sion. However, the liver is not the ideal site for islet sur-
vival after transplantation due to the instant blood-medi-
ated inflammatory reaction (IBMIR), hypoxia and in-
flammatory cytokine release by surrounding tissue in-
duced by capillary bed occlusion in hepatic microvascu-
lature [63,64]. In addition islets implanted in the liver are
exposed to a non-native mechanical stress and exposure
to toxins filtered through the liver that further impedes
islet survival and function [65,66]. Other promising al-
ternative sites currently being explored include subcuta-
neous, intramuscular, omental, and bone marrow sites
[46,67-71].
In conclusion, current work has demonstrated apop-
tosis of β cell in patients with chronic pancreatitis d ue to
inflammation and inflammatory cytokines. These find-

H. S. Dong et al. / Advances in Bioscience and Biotechnology 3 (2012) 782-787 785
ings serve to explain the late onset of diabetes in patients
with long-standing chronic pancreatitis. When islets in
patients with chronic pancreatitis are autologously trans-
planted, additional islet stressors result in β cell loss
through apoptosis. Strategies that can prevent β cell
death during these processes can benefit patients with
chronic pancreatitis and perhaps more importantly lead
to new understanding of diabetes of all causes.
6. ACKNOWLEDGEMENTS
This study was supported in part by the South Carolina Clinical &
Translational Research (SCTR) Institute, with an academic home at the
Medical University of South Carolina CTSA, NIH/NC RR Grant Num-
ber UL1RR029882 and the JDRF grant 5-2012-149 (to H.W. and
D.A.).
REFERENCES
[1] Talukdar, R., Saikia, N., Singal, D.K. and Tandon, R.
(2006) Chronic pancreatitis: Evolving paradigms. Pan-
creatology, 6, 440-449. doi:10.1159/000094561
[2] Dixon, E., Graham, J.S., Sutherland, F. and Mitchell, P.C.
(2004) Splenic injury following endoscopic retrograde
cholangiopancreatography: A case report and review of
the literature. Journal of the Society of Laparoendoscopic
Surgeons, 8, 275-277.
[3] Manciu, N., Beebe, D.S., T ran, P., Gruessner, R., Suther-
land, D.E. and Belani, K.G. (1999) Total pancreatectomy
with islet cell autotransplantation: Anesthetic implica-
tions. Journal of Clinical Anesthesia, 11, 576-582.
doi:10.1016/S0952-8180(99)00100-2
[4] Dixon, J., DeLegge, M., Morgan, K.A. and Adams, D.B.
(2008) Impact of total pancreatectomy with islet cell
transplant on chronic pancreatitis management at a dis-
ease-based center. The American Surgeon, 74, 735-738.
[5] Wahoff, D.C., Papalois, B. E., Najarian, J.S., et al. (1995)
Autologous islet transplantation to prevent diabetes after
pancreatic resection. Annals of Surgery, 222, 562-575.
[6] Bhanot, U.K. and Moller, P. (2009) Mechanisms of par-
enchymal injury and signaling pathways in ectatic ducts
of chronic pancreatitis: Implications for pancreatic car-
cinogenesis. Laboratory Investigation, 89, 489-497.
doi:10.1038/labinvest.2009.19
[7] Schrader, H., et al. (2009) Reduced pancreatic volume
and beta-cell area in patients with chronic pancreatitis.
Gastroenterology, 136, 513-522.
doi:10.1053/j.gastro.2008.10.083
[8] Mitchell, R.M., Byrne, M.F. and Baillie, J. (2003) Pan-
creatitis. Lancet, 361, 1447-1455.
doi:10.1016/S0140-6736(03)13139-X
[9] Mitnala, S., Pondugala, P.K., et al. (2010) Reduced ex-
pression of PDX-1 is associated with decreased beta cell
function in chronic pancreatitis. Pancreas, 39, 856-862.
doi:10.1097/MPA.0b013e3181d6bc69
[10] Davalli, A.M., Scaglia, L., Zangen, D.H., et al. (1996)
Vulnerability of islets in the immediate posttransplanta-
tion period. Dynamic changes in structure and function,
Diabetes, 45, 1161-1167.
doi:10.2337/diabetes.45.9.1161
[11] Cui, Y. and Andersen, D.K. (2011) Pancreatogenic dia-
betes: Special considerations for management. Pancrea-
tology: Official Journal of the International Association
of Pancreatology, 11, 279-294.
doi:10.1159/000329188
[12] Lankisch, P.G. (2001) Natural course of chronic pan-
creatitis. Pancreatology: Official Journal of the Interna-
tional Association of Pancreatology, 1, 3-14.
doi:10.1159/000055786
[13] Bateman, A.C., Turner, S.M., et al. (2002) Apoptosis and
proliferation of acinar and islet cells in chronic pancreati-
tis: Evidence for differential cell loss mediating preserva-
tion of islet function. Gut, 50, 542-548.
doi:10.1136/gut.50.4.542
[14] Hasel, C., Rau, B., et al. (2001) Differential and mutually
exclusive expression of CD95 and CD95 ligand in epithe-
lia of normal pancreas and chronic pancreatitis. Journal
of Technical Methods and Pathology, 81, 317-326.
[15] Hasel, C., Durr, S., et al. (2003) In chronic pancreatitis,
widespread emergence of TRAIL receptors in epithelia
coincides with neoexpression of TRAIL by pancreatic
stellate cells of early fibrotic areas. Journal of Technical
Methods and Pathology, 83, 825-836.
[16] Lamhamedi-Cherradi, S.E., Zheng, S., Tisch, R.M. and
Chen, Y.H. (2003) Critical roles of tumor necrosis fac-
tor-related apoptosis-inducing ligand in type 1 diabetes.
Diabetes, 52, 2274-2278.
doi:10.2337/diabetes.52.9.2274
[17] Bhanot, U.K. and Moller, P. (2009) Mechanisms of par-
enchymal injury and signaling pathways in ectatic ducts
of chronic pancreatitis: Implications for pancreatic car-
cinogenesis. Journal of Technical Methods and Patho-
logy, 89, 489-497.
[18] Degli-Esposti, M.A., Dougall, W.C., et al. (1997) The
novel receptor TRAIL-R4 induces NF-kappaB and pro-
tects against TRAIL-mediated apoptosis, yet retains an
incomplete death domain. Immunity, 7, 813-820.
doi:10.1016/S1074-7613(00)80399-4
[19] Chen, X., Ji, B., Han, B., Ernst, S.A., Simeone, D. and
Logsdon, C.D. (2002) NF-kappaB activation in pancreas
induces pancreatic and systemic inflammatory response.
Gastroenterology, 122, 448-457.
doi:10.1053/gast.2002.31060
[20] Butler, A.E., Janson, J. , et al. (2003) Beta-cell de ficit and
increased beta-cell apoptosis in humans with type 2 dia-
betes. Diabetes, 52, 102-110.
doi:10.2337/diabetes.52.1.102
[21] Donath, M.Y., Storling, J., et al. (2008) Cytokines and
beta-cell biology: From concept to clinical translation.
Endocrine Reviews, 29, 334-350.
doi:10.1210/er.2007-0033
[22] Tandon, R.K. and Garg, P.K. (2011) Oxidative stress in
chronic pancreatitis: Pathophysiological relevance and
management. Antioxidants & Redox Signaling, 15, 2757-
2766. doi:10.1089/ars.2011.4115
[23] Pavan Kumar, P., Radhika, G., et al. (2012) Interferon

H. S. Dong et al. / Advances in Bioscience and Biotechnology 3 (2012) 782-787 786
gamma and glycemic status in diabetes associated with
chronic pancreatitis. Pancreatology, 12, 65-70.
[24] Mitnala, S., Pondugala, P.K., et al. (2010) Reduced ex-
pression of PDX-1 is associated with decreased beta cell
function in chronic pancreatitis. Pancreas, 39, 856-862.
doi:10.1097/MPA.0b013e3181d6bc69
[25] Blondet, J.J., Carlson, A.M., et al. (2007) The role of
total pancreatectomy and islet autotransplantation for
chronic pancreatitis. The Surgical clinics of North Ame-
rica, 87, 1477-1501. doi:10.1016/j.suc.2007.08.014
[26] Argo, J.L., Contreras, J.L., Wesley, M.M. and Christein,
J.D. (2008) Pancreatic resection with islet cell autotrans-
plant for the treatment of severe chronic pancreatitis. The
American Surgeon, 74, 530-536.
[27] Nath, D.S., Kellogg, T.A. and Sutherland, D.E. (2004)
Total pancreatectomy with intraportal auto-islet trans-
plantation using a temporarily exteriorized omental vein.
Journal of the American College of Surgeons, 199, 994-
995. doi:10.1016/j.jamcollsurg.2004.07.033
[28] Bellin, M.D. and Sutherland, D.E. (2010) Pediatric islet
autotransplantation: Indication, technique, and outcome.
Current Diabetes Reports, 10, 326-331.
doi:10.1007/s11892-010-0140-4
[29] Kobayashi, T., Manivel, J.C., et al. (2011) Correlation of
histopathology, islet yield, and islet graft function after
islet autotransplantation in chronic pancreatitis. Pancreas,
40, 193-199. doi:10.1097/MPA.0b013e3181fa4916
[30] Farney, A.C., Najarian, J.S., et al. (1991) Autotransplan-
tation of dispersed pancreatic islet tissue combined with
total or near-total pancreatectomy for treatment of chro-
nic pancreatitis. Surgery, 110, 427-437.
[31] Robertson, R.P., Lanz, K.J., et al. (2001) Prevention of
diabetes for up to 13 years by autoislet transplantation
after pancreatectomy for chronic pancreatitis. Diabetes,
50, 47-50. doi:10.2337/diabetes.50.1.47
[32] Biarnes, M., Montolio, M., et al. (2002) Beta-cell death
and mass in syngeneically transplanted islets exposed to
short- and long-term hyperglycemia. Diabetes, 51, 66-72.
doi:10.2337/diabetes.51.1.66
[33] Ahn, Y.B., Xu, G., et al. (2007) Changes in gene expres-
sion in beta cells after islet isolation and transplantation
using laser-capture microdissection. Diabetologia, 50,
334-342.
doi:10.1007/s00125-006-0536-5
[34] Davalli, A.M., Scaglia, L., et al. (1995) Early changes in
syngeneic islet grafts: effect of recipient’s metabolic con-
trol on graft outcome. Transplantation Proceedings, 27,
3238-3239.
[35] Bhardwaj, P., Thareja, S., et al. (2004) Micronutrient
antioxidant intake in patients with chronic pancreatitis,
Tropical gastroenterology. Journal of the Digestive Dis-
eases Foundation, 25, 69-72.
[36] Hsu, J.T., Yeh, C.N., et al. (2005) Outcome of pancreati-
coduodenectomy for chronic pancreatitis. Journal of the
Formosan Medical Association, 104, 811-815.
[37] Ong, S.L., Gravante, G., et al. (2009) Total pancreatec-
tomy with islet autotransplantation: an overview. Journal
of the International Hepato Pancreato Biliary Associa-
tion, 11, 613-621.
doi:10.1111/j.1477-2574.2009.00113.x
[38] Howes, N., Lerch, M.M., et al. (2004) Clinical and ge-
netic characteristics of hereditary pancreatitis in Europe.
Clinical Gastroenterology and Hepatology, 2, 252-261.
doi:10.1016/S1542-3565(04)00013-8
[39] Ammann, R.W. (2006) Diagnosis and management of
chronic pancreatitis: Current knowledge. Swiss Medical
Weekly, 136, 166-174.
[40] De Cock, H.E., Forman, M.A., et al. (2007) Prevalence
and histopathologic characteristics of pancreatitis in cats.
Veterinary Pathology, 44, 39-49.
doi:10.1354/vp.44-1-39
[41] Wang, H., Ferran, C., et al. (2011) Induction of protective
genes leads to islet survival and function. Journal of
Transplantation, 2011, 141898.
doi:10.1155/2011/141898
[42] Wang, H., Wu, H., et al. (2012) Activation of peroxisome
proliferator-activated receptor gamma prolongs islet al-
lograft survival, cell transplantation. Cell Transplant, 21,
2111-2118.
[43] Emamaullee, J.A. and Shapiro, A.M. (2006) Interven-
tional strategies to prevent beta-cell apoptosis in islet
transplantation. Diabetes, 55, 1907-1914.
doi:10.2337/db05-1254
[44] Grey, S.T., Arvelo, M.B., et al. (1999) A20 inhibits cyto-
kine-induced apoptosis and nuclear factor kappaB-de-
pendent gene activation in islets. The Journal of Experi-
mental Medicine, 190, 1135-1146.
doi:10.1084/jem.190.8.1135
[45] Riachy, R., Vandewalle, B., et al. (2002) 1,2,5-dihy-
droxyvitamin D3 protects RINm5F and human islet cells
against cytokine-induced apoptosis: Implication of the
antiapoptotic protein A20. Endocrinology, 143, 4809-
4819. doi:10.1210/en.2002-220449
[46] Christoffersson, G., Carlsson, P.O. and Phillipson, M.
(2011) Intramuscular islet transplantation promotes re-
stored islet vascularity. Islets, 3, 69-71.
doi:10.4161/isl.3.2.14997
[47] Basta, G. and Calafiore, R. (2011) Immunoisolation of
pancreatic islet grafts with no recipient’s immunosup-
pression: Actual and future perspectives. Current Diabe-
tes Reports, 11, 384-391.
doi:10.1007/s11892-011-0219-6
[48] Fort, A., Fort, N., et al. (2008) Biohybrid devices and
encapsulation technologies for engineering a bioartificial
pancreas. Cell Transplantation, 17, 997-1003.
doi:10.3727/096368908786991498
[49] Giraldo, J.A., Weaver, J.D. and Stabler, C.L. (2010) Tis-
sue engineering approaches to enhancing clinical islet
transplantation through tissue engineering strategies.
Journal of Diabetes Science and Technology, 4, 1238-
1247.
[50] Trivedi, N., Keegan, M., et al. (2001) Islets in alginate
macrobeads reverse diabetes despite minimal acute insu-
lin secretory responses. Transplantation, 71, 203-211.
doi:10.1097/00007890-200101270-00006
[51] van Schilfgaarde, R. and de Vos, P. (1999) Factors influ-

H. S. Dong et al. / Advances in Bioscience and Biotechnology 3 (2012) 782-787 787
encing the properties and performance of microcapsules
for immunoprotection of pancreatic islets. Journal of
Molecular Medicine, 77, 199-205.
doi:10.1007/s001090050336
[52] Sandberg, J.O., Olsson, N., et al. (1995) Immunosuppres-
sion, macroencapsulation and ultraviolet-B irradiation as
immunoprotection in porcine pancreatic islet xenotrans-
plantation. Pharmacology & Toxicology, 76, 400-405.
doi:10.1111/j.1600-0773.1995.tb00169.x
[53] Pollok, J.M., Ibarra, C., et al. (1998) Immuno-isolation of
xenogenic islands of Langerhans in a tissue engineered
autologous cartilage capsule. Zentralblatt fur Chirurgie,
123, 830-833.
[54] Qi, M., Gu, Y., et al. (2004) PVA hydrogel sheet macro-
encapsulation for the bioartificial pancreas. Biomaterials,
25, 5885-5892. doi:10.1016/j.biomaterials.2004.01.050
[55] Teramura, Y. and Iwata, H. (2008) Islets surface modifi-
cation prevents blood-mediated inflammatory responses.
Bioconjugate Chemistry, 19, 1389-1395.
doi:10.1021/bc800064t
[56] Lee, D.Y., Park, S.J., et al. (2007) Highly poly(ethylene)
glycolylated islets improve long-term islet allograft sur-
vival without immunosuppressive medication. Tissue En-
gineering, 13, 2133-2141. doi:10.1089/ten.2006.0009
[57] Basarkar, A. and Singh, J. Poly (2009) (lactide-co-gly-
colide)-polymethacrylate nanoparticles for intramuscular
delivery of plasmid encoding interleukin-10 to prevent
autoimmune diabetes in mice. Pharmaceutical Research,
26, 72-81.
[58] Mao, G.H., Chen, G.A., et al. (2009) The reversal of
hyperglycaemia in diabetic mice using PLGA scaffolds
seeded with islet-like cells derived from human embry-
onic stem cells. Biomaterials, 30, 1706-1714.
doi:10.1016/j.biomaterials.2008.12.030
[59] Jain, R., Shah, N.H., et al. (1998) Controlled drug deli-
very by biodegradable poly(ester) devices: Different pre-
parative approaches. Drug Development and Industrial
Pharmacy, 24, 703-727.
doi:10.3109/03639049809082719
[60] Jain, R.A. (2000) The manufacturing techniques of vari-
ous drug loaded biodegradable poly(lactide-co-glycolide)
(PLGA) devices. Biomaterials, 21, 2475-2490.
doi:10.1016/S0142-9612(00)00115-0
[61] Lu, J.M., Wang, X., et al. (2009) Current advances in
research and clinical applications of PLGA-based nano-
technology. Expert Review of Molecular Diagnostics, 9,
325-341. doi:10.1586/erm.09.15
[62] Athanasiou, K.A., Niederauer, G.G. and Agrawal, C.M.
(1996) Sterilization, toxicity, biocompatibility and clini-
cal applications of polylactic acid/polyglycolic acid co-
polymers. Biomaterials, 17, 93-102.
doi:10.1016/0142-9612(96)85754-1
[63] Yin, D., Ding, J.W., et al. (2006) Liver ischemia contri-
butes to early islet failure following intraportal transplant-
tation: Benefits of liver ischemic-preconditioning. Ameri-
can Journal of Transplantation, 6, 60-68.
doi:10.1111/j.1600-6143.2005.01157.x
[64] Wilson, J.T. and Chaikof, E.L. (2008) Thrombosis and
inflammation in intraportal islet transplantation: A review
of pathophysiology and emerging therapeutics. Journal of
Diabetes Science and Technology, 2, 746-759.
doi:10.1097/01.tp.0000290388.70019.6e
[65] Cardani, R., Pileggi, A., et al. (2007) Allosensitization of
islet allograft recipients. Transplantation, 84, 1413-1427.
[66] Rickels, M.R., Kamoun, M., et al. (2007) Evidence for
allograft rejection in an islet transplant recipient and ef-
fect on beta-cell secretory capacity. The Journal of Cli-
nical Endocrinology and Metabolism, 92, 2410-2414.
doi:10.1210/jc.2007-0172
[67] Lund, T., Korsgren, O., et al. (2010) Sustained reversal of
diabetes following islet transplantation to striated muscu-
lature in the rat. The Journal of Surgical Research, 160,
145-154. doi:10.1016/j.jss.2008.11.009
[68] Salazar-Banuelos, A., Wright, J.R., et al. (2008) Pancre-
atic islet transplantation into the bone marrow of the rat.
American Journal of Surgery, 195, 674-678.
doi:10.1016/j.amjsurg.2007.12.040
[69] Berman, D.M., O’Neil, J.J., et al. (2009) Long-term sur-
vival of nonhuman primate islets implanted in an omental
pouch on a biodegradable scaffold. American Journal of
Transplantation, 9, 91-104.
doi:10.1111/j.1600-6143.2008.02489.x
[70] van der Windt, D.J., Echeverri, G.J., et al. (2008) The
choice of anatomical site for islet transplantation. Cell
Transplantation, 17, 1005-1014.
doi:10.3727/096368908786991515
[71] Pileggi, A., Molano, R.D., et al. (2006) Reversal of dia-
betes by pancreatic islet transplantation into a subcuta-
neous, neovascularized device. Transplantation, 81, 1318-
1324. doi:10.1097/01.tp.0000203858.41105.88