Hindawi Publishing Corporation
Advances in Urology
Volume 2012, Article ID 653652, 7 pages
TheUseof RegenerativeMedicineintheManagement of
Matthew E.Hyndman,1DeborahKaye,2Nicholas C.Field,1KeithA.Lawson,1
Norm D.Smith,3GaryD.Steinberg,3Mark P.Schoenberg,2andTrinityJ. Bivalacqua2
1Southern Alberta Institute of Urology, University of Calgary, Alberta, Canada T2V 1P9
2The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21287-2101, USA
3University of Chicago Medical Center, Chicago, IL 60637, USA
Correspondence should be addressed to Trinity J. Bivalacqua, email@example.com
Received 11 June 2012; Accepted 1 August 2012
Academic Editor: Nan-Haw Chow
Copyright © 2012 Matthew E. Hyndman et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Muscle invasive and recurrent nonmuscle invasive bladder cancers have been traditionally treated with a radical cystectomy and
urinary diversion. The urinary diversion is generally accomplished through the creation of an incontinent ileal conduit, continent
catheterizable reservoir, or orthotopic neobladder utilizing small or large intestine. While radical extirpation of the bladder is
often successful from an oncological perspective, there is a significant morbidity associated with enteric interposition within the
genitourinary tract. Therefore, there is a great opportunity to decrease the morbidity of the surgical management of bladder
cancer through utilization of novel technologies for creating a urinary diversion without the use of intestine. Clinical trials using
neourinary conduits (NUC) seeded with autologous smooth muscle cells are currently in progress and may represent a significant
surgical advance, potentially eliminating the complications associated with the use of gastrointestinal segments in the urinary
reconstruction, simplifying the surgical procedure, and greatly facilitating recovery from cystectomy.
An estimated 73,510 people in the United States will be
diagnosed with bladder cancer resulting in approximately
14,880 deaths in 2012 . It is the fifth most common
cancer in the United States and is responsible for 3% of all
cancer deaths. Bladder cancer is 3-4 times more prevalent
amongst males than females. White males and females are
than African American males and females. Disease incidence
peaks in the 8th decade of life [2–4]. The percentage of
patients with invasive cancer also increases with age. The
incidence of invasive bladder cancer in men greater than 70
years old is 3.5% compared to 0.41% amongst 40–59-year-
old males .
Bladder cancer is hypothesized to occur because of a
variety of factors, including carcinogen exposure, radiation,
chemotherapy, infection, inflammation, nutrition, genetics,
and geography. However, the polygenetic basis of bladder
cancer is linked to various genetic mutations. Thelen and
Schaeuble were the first authors to describe a familial
occurrence of bladder cancer; however, a familial syndrome
has not been described . An extensive number of genes
have been hypothesized to play a role in bladder cancer
etiology and prognosis, including chromosome 9 deletions,
RAS gene mutations, P53, and Rb [6, 7]. Some of these
mutations are common in many types of bladder cancer,
while others are more specific to nonmuscle invasive or
muscle-invasive disease. Genetic polymorphisms, including
the slow NAT-2 polymorphism and null variant glutathione-
s-transferase polymorphism may also play a role in bladder
cancer, although the outcome data for these polymorphisms
is mixed .
Environmental exposures are known causes of bladder
cancer. An estimated 20–27% of bladder cancers are associ-
ated with industrial exposure. Rubber workers have some of
the highest incidence of bladder cancer (RR 1.29, CI 1.06–
1.58) . These exposures can occur in a variety of fashions
2 Advances in Urology
including through-skin absorption or inhalation. There is
a long latency period between environmental exposure and
bladder cancer diagnosis, thereby making a specific etiology
of bladder cancer difficult to determine .
Tobacco smoke is associated with a 2–6 times increase
in the relative risk of bladder cancer. Aromatic amines,
common in certain dyes and arsenic, a common pollutant,
to be associated with bladder cancer, especially chronic
with squamous and transitional cell cancer .
Treatment for bladder cancer varies by disease stage.
While low-grade disease can often be treated with local
resection and intravesical immunotherapy or chemotherapy,
muscle-invasive disease usually requires cystectomy with or
without neoadjuvant or adjuvant chemotherapy. Primary
metastatic disease .
Since the original report by Whitmore and Marshall ,
surgical extirpation of the bladder has become the gold
an important treatment option for some nonmuscle invasive
tumors. Bladder reconstruction and urinary diversion have
been performed utilizing various gastrointestinal segments,
however the vast majority of reconstructive procedures used
today still involve either the ileum or colon. While numerous
conduit, continent cutaneous diversions, and orthotropic
neobladder diversion. The majority of postoperative com-
plications related to direct surgical problems associated
with the ureterointestinal anastomosis, bowel anastomosis,
infection/abscess, or metabolic disturbances related to urine
directly contacting the absorptive gastrointestinal tract [17–
19]. Stomal complications are also observed and are linked
to peri-stomal ischemia and subsequent fibrosis .
Although complication rates for radical cystectomy are
believed to be declining, it is still associated with significant
morbidity and mortality. Prior to 1990, morbidity and
mortality rates were 28–42% and 2.4–15%, respectively.
Current morbidity and mortality rates have decreased to
11–68% and 0–3.9%, respectively . Using the Clavien
grading system, a recent study by Shabsigh, found that 64%
of patients experienced a complication within 90 days of
surgery, of which 13% were high grade (grade 3–5) defined
as a complication requiring an operative intervention (grade
3) or resulting in significant disability (grade 4) or death
(grade 5) . Another study by Stimson et al. found that
26.6% of patients were readmitted within 90 days of a radical
cystectomy, of these, 19.7% were admitted within 30 days
of surgery. Ileus, pyelonephritis, and urinary tract infections
were the most common reasons for early readmission,
while pyelonephritis was the most common reason for late
readmission . Complication rates were recently found to
increase with age, male gender, nonteaching hospitals, and
hospital surgical volumes .
across different studies, and across different types of urinary
diversion. Complication reporting is not standardized and
the length of followup varies greatly across studies. However,
across studies some complications are more common than
others. Gastrointestinal complications, including paralytic
ileus, small bowel obstructions, emesis, gastritis, and gastric
ulcers are often most common (29%), followed by infections
(25%) and wound complications (15%) . Infectious
complications range from urinary tract infections (12.8%)
to septicemia (9.6%) . Wound complications also pose
a significant concern. Roughly 0–15% of patients will
have a wound infection and 0–9% of patients may suffer
from wound dehiscence . Overall, major complications
related to the use of the gastrointestinal tract for urinary
reconstruction. Other complications include, but are not
limited to blood loss and transfusion, urinary extravasation
and leak, infections, deep vein thrombosis and pulmonary
embolism, intestinal or anastomotic leak, cardiac complica-
tions, metabolic disturbances, strictures, and lymphoceles.
Many of the short and long term surgical complications
result from replacement of organs designed primarily for
storage and excretion with organs which are specialized
absorptive structures. The GI tract, especially the small
bowl, is microscopically arranged to maximize absorptive
surface area with villi and microvilli. Indeed, reabsorption
of urine and solutes may lead to a hyperchloremic metabolic
acidosis. While usually subclinical, electrolyte abnormalities
are in part dependent on the surface area of the diversion.
Therefore, patients with diversions requiring more bowl,
such as neobladders are more likely to have electrolyte
abnormalities. Other metabolic alterations related to urinary
diversion include vitamin B12 deficiency decreased entero-
hepatic recycling of bile salts, and dysregulation of calcium
metabolism. Reabsorption of renal excreted medication also
results from interposition of the GI tract within the GU
The degree of postoperative morbidity associated with
radical cystectomy suggests that there is a genuine oppor-
tunity to improve treatment-related outcomes through the
adoption of novel and innovative reconstructive technolo-
3.Use of Regenerative Technology inMedicine
Regenerative medicine involves replacing or restoring dam-
aged, absent, or dysfunctional tissues. This emerging field
has the potential to impact human disease states such as
diabetes , Alzheimer’s , cardiovascular disease ,
and musculoskeletal disorders . Cell-based therapies
are primarily focused on restoring function rather than
generating new organ structures. Regeneration of complex
tissues presents an additional challenge where in addition to
restoring cellular function, the 3D tissue structure must also
be recapitulated. This structure is dependent on integrating
multiple cell types to create supportive vascular, nervous,
Advances in Urology3
lymphatic, and structural tissues. A number of approaches
are being actively studied to recreate extracellular matrices
and supportive tissues. One technique is to use decellularl-
or seed the ultrastructure with cells. Alternatively, porous
de novo ultrastructures can be synthesized and then seeded
with cells or both cells and matrixes using “ink jet” printing
technology with some success. The advantage of the later
techniques is that tailor-made shapes are possible. A matrix
seeded approach was recently utilized by Jungebluth et al.
for reconstruction of a trachea for a patient with recur-
rent bronchial carcinoma using a nanocomposite polymer
[30, 31]. The polymer was then seeded with autologous
mononuclear cells (MNC) harvested from a bone marrow
biopsy. This proof of concept study was successful and at last
followup the patient was tumor-free and symptom-free at
and then repopulated them with neonatal cardiomyocytes
and remarkably the repopulated hearts were able to generate
contractions . Furthermore, using an animal model,
Ross et al. repopulated a decellularized kidney with a mouse
embryonic cell line which demonstrated that a decellularized
ECM can, in part, direct the differentiation of pluripotent
cell lines . Animal studies, investigating whole corpora
replacement of decellularized penises, have been success-
fully repopulated and reimplanted with functionality .
Expanding these proofs of principle studies to recellulariza-
tion of complex human organs is complicated in part by
the larger size of human structures. Perfusion and nutrient
delivery to the seeded cells is dependent on the distance
from the microvasculature. Thicker structures, therefore,
require complex reendothelialization and revascularization
of the seeded ECM structures. Embryonic development of
organelles is not limited by this perfusion factor given that
organ growth and vascular growth expands proportionally.
The success of the aforementioned tracheal replacement
study is in part because of the tubular structure of the organs
which therefore limits the perfusion distance. Because of its
inherent tubular design, the urinary tract is an ideal system
for the application of regenerative medicine.
4.Use of Regenerative MedicineinUrology
Replacement or augmentation of the urinary tract has
use of interposing bowel in the urinary tract significantly
increases acute surgical complications and the absorptive
properties of bowel counteract the fundamental excretory
function of the urinary system. Synthetic substitutes have
failed primarily because of scaring, poor compliance, and
More recently, modifications of small intestine submucosa
have shown improved smooth muscle cell regeneration but
poor long-term maintenance of capacity . Interestingly,
bladder matrices preseeded with cells have improved func-
tional properties and decreased scaring and fibrosis com-
pared to unseeded augments . However, augments act as
after a radical cystectomy complicates organ restoration
because the entire functional organ including the supportive
vascular and nervous structures is removed. Seeding with
autologous bladder tissue is often complicated by the
possibility of seeding malignant cells.Therefore,regenerative
tissue replacement in the bladder cancer population requires
the synthesis of complex structures that ideally is seeded
with autologous cells from a source other than the native
Regenerative medicine principles have been successfully
applied to provide implantable cell-seeded matrices for use
in the reconstruction, repair, augmentation, or replacement
of laminarily organized luminial organs and tissue struc-
tures, such as a bladder or a bladder component, typically
composed of urothelial and smooth muscle cell layers [38–
42]. Smooth muscle cells (SMC) may be derived from
the patient’s own tissue, including the bladder, urethra,
ureter, and other urogenital tissue. However, there are
challenges associated with dependence upon the develop-
ment and maintenance of cell-culture systems from the
primary organ site as the basic unit for developing new
and healthy engineered tissues. A malignant organ, such
as a bladder with established urothelial carcinoma, or
utilizing undifferentiated pluripotent cells is not appropriate
for sourcing cells populating neoorgans. However, using
alternative sources of differentiated mature cells for seeding
synthetic, biodegradable tubular scaffold structures for de
novo formation of urinarylike neotissue in vivo may be a
more suitable approach.
With regenerative technologies, stable SMC may be used
to seed synthetic, biodegradable tubular scaffold structures.
With implantation of these seeded scaffolds, the body can
tissue, that is, histologically identical to native urinary tissue
[39, 43]. The ability to create urologic structures de novo
from scaffolds seeded by autologous smooth muscle cells will
technologies into clinical practice.
Using SMC and synthetic scaffolds, complete blad-
der replacements have been designed and implanted to
regenerate a complete, innervated, and pharmacologically
intact urinary bladder in animals . A conduit from the
ureters to the skin surface addresses the current standard
of care while simplifying the surgical procedure and may
also provide improved patient outcomes. Tengion’s neo-
urinary conduit (NUC) serves as a template to catalyze the
regeneration of native-like urinary tissue that can connect
theureterstotheskin surface.To ensurenative urinary tissue
regeneration, a biocompatible and biodegradable scaffold
with an extended history of safety and clinical utility is
necessary. The broadly used scaffold polylactate-glycolate
(PLGA) serves the objective to enhance tissue regeneration
and promote neotissue integration into the body when
properly seeded with SMCs.
Construction of the NUC is based upon two principal
of PGA polymer mesh fashioned into the required tubular
4 Advances in Urology
shape and coated with a 50/50 blend of PLGA copolymer.
Specific structural parameters may be modified as needed
during the surgical procedure to personalize the application
to a patient’s needs. The choice of well-established, synthetic,
and degradable biopolymers reflects the same requirements
for reliability and reproducibility inherent in the choice
of these polymers for applications in other bladder-related
neoorgans. (ii) Cells. Autologous smooth muscle cells (SMC)
sourced from bladder or nonbladder tissue may potentially
be applied for construction of NUC.
Based on the successful outcomes in experimental
conditions using a porcine cystectomy model, Tengion
has initiated Phase I clinical trials of NUC constructs in
human patients requiring urinary diversion. This Phase I
study “Incontinent Urinary Diversion Using an Autologous
show/NCT01087697) is currently recruiting patients, with
the objective of implanting up to 10 patients by the end
of 2012. The objective of the study is to evaluate if NUC
constructs (made using autologous adipose-derived SMCs in
combination with defined degradable biomaterial scaffolds)
can form a functional conduit to safely facilitate passage
of urine from kidneys subsequent to radical cystectomy.
Primary outcome indices over a 12-month postimplantation
tim eframe include structural integrity and conduit patency.
CT scans will be used to demonstrate that urine may flow
safely through the NUC construct. Additional measures
of primary outcomes up to 12-months postimplantation
include an evaluation of any product- or procedure-related
to adverse events. Similarly, secondary outcome indices will
include analysis of NUC structural integrity and patency
over a 12–60-month postimplantation time frame. CT
scan and renal ultrasound will be applied to demonstrate
that urine flows safely through the NUC construct up to
60-month afterimplantation. Procedural- and product-
related adverse events will also be monitored to 60 months
afterimplantation. Finally, the overall safety of the NUC
procedural-related adverse events and patient vital signs.
5.1. Future Directions. The use of tissue engineered (TE)
bladders as functionally superior alternatives to enteric
urinary diversions, which are currently utilized by urologists
to reconstruct the genitourinary tract, offers great promise
to patients. However, a number of barriers exist that must
be overcome before this technology can be successfully
ment of a mature blood supply to TE structures represents
arguably the largest of these barriers as poorly vascularized
tissue grafts have the propensity to develop scar tissue as a
result of hypoxia, leading to decreased bladder contractility,
compliance and overall function [45–47]. As such, great
efforts to improve the efficiency of neoangiogenesis within
TE bladders have been undertaken by scientists in the field.
To date, a number of tissue engineering strategies have been
employed in both urologic and nonurologic tissue grafts
towards this goal. All have been developed based on our
increased knowledge of the physiological parameters that
regulate and promote blood-vessel formation and stability.
Of these, the use of endothelial support cells, vascular
promoting growth factors and proangiogenic extracellular
matrix properties standout as the most promising novel
5.2. Endothelial Support Cells. The development of a mature
vascular network within tissue grafts requires extensive
communication of endothelial cells with their surrounding
microenvironment. Central to this are endothelial support
cells known as pericytes. These cells mediate blood vessel
formation, maturation, and stabilization through their abil-
ity to regulate endothelial cell differentiation and growth
via direct cell-to-cell contact and paracrine signaling .
Due to this critical support role, it is obvious that strategies
to improve pericyte coverage of forming vascular networks
hold promise. While the implantation of pericytes, directly
on grafts is the most intuitive approach, a reliable source of
by Traktuev et al. has demonstrated the ability to utilize a
CD34 positive subpopulation of adipose stromal cells (ASC)
to stabilize endothelial cell networks . Within adipose
perivascular and, like pericytes, is capable of communicating
via paracrine signaling to endothelial cells. Interestingly,
in vitro leads to stable vascular network assembly. Further-
more, matrigel and confocal microscopy revealed their over-
laying localization, highlighting the ability to utilize ASCs
to promote stable vascularization. In a subsequent study,
these authors demonstrated the superiority of coimplanting
both ASC with EPC to improve collagen graft implant
vascularization in SCID/NOD mice relative to ASC or EPC
alone, portraying the advantages of enhancing endothelial
support as a strategy to improve graft neoangiogenesis .
To date, this strategy has yet to be employed in improving
bladder organogenesis and as such, the implantation of
adipose stromal cells into bladder scaffolds warrants further
investigation for improving vascularization and prevention
of scarring in TE bladders.
5.3. Growth Factors. The extracellular microenvironment
represents the medium by which endothelial and support
cells interact to orchestrate the complex physiological task
of forming new vascular networks. Within this medium,
an extensive array of molecular constituents exist which
act to drive the necessary signaling pathways between these
cells. Most notable, is the vascular endothelial growth factor
(VEGF), which has been extensively shown to be crucial
in promoting and regulating angiogenesis . Within the
endothelial cell microenvironment, VGEF is organized in a
precise manner in order to allow for the intricate regulation
of blood-vessel tubulogenesis and maturation. Interestingly,
with the progress made in the field of nanotechnology
it is now possible to design scaffolds for organogenesis
which are capable of modeling this complexity . Indeed,
micropatterning techniques have been utilized to create scaf-
folds (hydrogels) embedded with VEGF. These hydrogels are
hydrophilic, allowing them to resist growth factor (protein)
Advances in Urology5
absorption as well as nonspecific cell adhesion . More-
over, by introducing collagenase sensitive peptide sequences
and covalently immobilizing VEGF into the back bone of
the hydrogel, an endothelial cell controlled local release of
growth factor can be achieved . Further regulation of
through embedding of cell adhesive peptide sequences, such
as Arg-Gly-Asp-Ser (RDGS), to control where endothelial
cell attachment and therefore, liberation of VEGF occurs
[53, 54]. Of note, the use of this growth-factor-imbedded
hydrogel has been shown to not only improve endothelial
tubulogenesis, but also enhance endothelial cell motility
and formation of intercellular contacts . Importantly,
the release of growth factors from an elastomeric poly
(1,8-octanediol-co-citrate) (POC) scaffold, which has been
utilized in tissue engineering of bladder tissue, has also been
described . In their study, Sharma et al. developed an
elastomeric POC scaffold modified with heparin sulphate
that was capable of releasing VEGF, fibroblast growth factor
2 and insulin growth factor 1. The use of this VEGF releasing
scaffold resulted in augmentation of scaffold vascularization
compared to control when implanted in nude (athymic) rats
as demonstrated by an increase in CD31 and von willebrand
factor (vWF) immunostaining. Thus, the application of this
technology to the development of TE bladders holds great
promise in improving their clinical functionality and there-
factors may be simultaneously released as demonstrated by a
recent study by Davies et al. who delivered both VGEF and
to maintain graft angiogenesis in vivo .
5.4. Extracellular Matrix Properties. Beyond growth fac-
tors, many other extracellular matrix (ECM) components
contribute to the growth regulation and maturation of
proangiogenic effectsof nongrowth factorECM components
by Caiado et al. who characterized the ability of fibrin E, a
known byproduct of ECM fibrin degradation, to enhance
vasculogenesis and wound healing . These authors
demonstrated that culture of EPC in ECM containing fibrin
E lead to increased adhesion, proliferation, and acquisition
of mature endothelial cell markers in vitro. Moreover,
when scaffolds enriched for fibrin E were tested against
integra scaffold controls in a murine Balb-c/SCID wound
healing model, they produced marked increases in neovessel
formation and facilitated greater wound closure. As such, it
is clear that nongrowth factor ECM components contribute
to vascularization of grafted tissue. Determination of the
ECM constituents that best promote vascularization of TE
bladders and subsequently, constructing bladder scaffolds
to incorporate these should be investigated. Furthermore,
the physical properties of the ECM that also contribute
to vasculogenesis of engineered scaffolds must also be
considered in the design of future bladder scaffolds. This is
highlighted by the finding that modulating the collagen fibril
density within scaffold matrices, which changes the scaffolds
stiffness properties, has dramatic effects on endothelial
colony forming cell (ECFC) vessel formation in vitro and in
vivo . Interestingly, when ECFC are cultured on matrices
with higher collagen fibril density and increased matrix
stiffness and transplanted into nude mice, an increase in the
average vessel area and total vascular area is seen, relative to
lower collagen fibril density matrixes . Hence, the design
of TE bladder scaffolds may benefit from incorporating both
neoangiogenic promoting ECM components (i.e., growth
factors,fibrin, etc.) as well as pro-vasculogenic ECM physical
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significant postoperative morbidity. Recent advances in
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a conduit rather than an entire bladder may represent
an alternative to the use of gastro-intestinal tissue for
post-cystectomy urinary diversion and therefore decrease
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