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Indian
Institute Of Science, Bangalore Offers Technology For
Antimicrobial Polymeric Material To Be Used For Urological
Reconstruction
Dynamically Cross Linked
Polydimethylsiloxane-Based Polyurethanes With
Contact-Killing Antimicrobial Properties As Implantable
Alloplasts For Urological Reconstruction
Introduction
Urological disorders, including bladder carcinoma,
interstitial cystitis, radiation injuries, accidental
trauma, neurologic conditions, and other congenital
anomalies, are estimated to affect over 400 million people
worldwide. Such conditions commonly necessitate surgical
intervention, wherein the diseased tissue is resected, and
reconstructive surgery is performed to correct the
function- ally deficient urinary system. The current
standard procedure involves the replacement or
augmentation with a section of the pa- tient’s
gastrointestinal tract as an autologous graft for the
urinary bladder. Notably, the utilization of a distal
segment from the small intestine (ileum) remains the most
popular. This detached section is shaped into a conduit or
bladder patch/pouch and reanastomosed to the residual
native organ. However, the intestinal mucosa is intended
for the uptake of water, electrolytes, and other molecules
of digested food. It is accordingly lined with an
absorptive and mucus-producing
epithelium. This is contrary to the bladder epithelium’s
non-absorptive nature and leads to in- compatibility upon
chronic exposure to urine. Thus, the exchange of the two
conflicting surfaces is invariably fraught with many
short- and long-term clinical complications. Among these,
excessive mucus production, electrolytic imbalance,
metabolic disturbances, urolithiasis, chronic infections,
and secondary malignancies are most commonly reported.
To avoid the morbidity associated with the use of
gastrointestinal tract, several studies have been carried
out in quest of the ideal substitute. Prominently, three
categories of biodegradable matrices; acellular tissue
(bladder acellular matrix, small intestine submucosa),
natural (collagen, alginate, silk fibroin), and synthetic
(polyglycolic acid, polylactic-co-glycolic acid, polycapro-
lactone, polyurethanes) polymers are being investigated as
part of bladder tissue engineering research. The
most notable work has been reported by Atala’s
group, based upon autologous cells seeded
collagenpolyglycolic acid scaffolds for de novo
reconstitution of bladder tissue. While preliminary
results seemed promising, numerous dissuading outcomes and
challenges have been identified with bladder tissue
engineering, for instance, graft contracture, rupture or
premature structural collapse, urine leakage,
calcification, fibrosis, along with inadequate
vascularization and innervation. To this end, alloplastic
materials present an alternate and equally exciting area
of research. Biostable polymers, including polyethylene,
polyvinylchlor ide, silicone rubber,
polytetrafluoroethylene, and polyurethanes, have
been extensively studied for their performance in the
urinary environment. Of these, silicone has persisted in
being the gold standard on account of its superior
properties that ensure low toxicity, tissue reactivity,
and fouling. It had been exclusively utilized in all the
previous alloplastic bladder models and continues to be
the most popular candidate for commercially available
short- term urological implants. Nevertheless, silicone is
often found to be limited in its poor mechanical behavior.
The present work is aimed at designing a polymeric
alloplast with a combination of structural integrity,
clinically relevant antibacterial properties, and
cytocompatibility. A series of
thermoplastic polyurethanes (TPU) modified with
polydimethyl siloxane (PDMS) were formulated to accomplish
the same. TPU constitutes an extremely versatile class of
segmented copolymers, characterized by high tensile and
tear strength, elongation, and adaptability in terms of
chemistry and processing options.
The inclusion of low surface energy PDMS phase is a known
strategy to render the additional benefits of improved
hydrolytic stability and, thus, biostability. With regards
to this, we have adopted the unique methodology of dynamic
crosslinking that is characteristic to the fabrication of
high-performance thermoplastic vulcanizate (TPVs).
Briefly, PDMS is allowed to undergo in situ crosslinking
within the molten TPU matrix while micro-compounding.
Unlike previous reports, which are
essentially based upon the physical or van der Waal forces
assisted melt-mixing process, the three-dimensional
cross linking of PDMS within the
TPU promotes much stronger interfacial adhesion. To the
best of our knowledge, this distinct methodology to
combine the functional performance and processability of
TPU with the desired surface characteristics of PDMS, has
never been attempted in past. The compatibilized binary
blends are, thereby, endowed with physical properties
suitable to withstand large deformations, clinical
handling, and manipulation. Further, they are covalently
modified with quaternized ammonium, pyridinium, and
phosphonium compounds to generate contact-killing
antimicrobial surfaces that can successfully inhibit
urinary tract infections while retaining appropriate in
vitro cellular response.
Conclusions
In this work, we have developed the antibacterial silicone
(polydimethyl siloxane, PDMS) modified thermoplastic
polyurethane (TPU) as a potential material for permanent
urological implants. From the diverse set of experiments,
the following conclusions are summarized:
(a) The successful incorporation of silicone (PDMS, up to
40% weight) in TPU is harnessed through the unique
fabrication strategy of dynamic crosslinking under
tailored twin-screw extrusion conditions. These
compatibilized binary compositions can be processed and
shaped using injection or compression molding.
(b) A series of uniaxial tensile tests and dynamic
mechanical analyses establish the improvement in physical
properties of blends upon in situ crosslinking. The
combination of viscoelastic modulus and tensile
strength/modulus/elongation to failure is either superior
or in good agreement to the natural urological tissues,
indicating the potential biomechanical compatibility. The
suture retention measurements qualify the clinically
accepted criteria for surgical handling.
(c) The contact killing antimicrobial activity is imparted
to the representative TPU/PDMS: 80/20 system through the
covalent grafting of three different cationic moieties,
namely 4-vinyl pyridine, branched polyethyleneimine, and
polyethyleneimine grafted (acrylic acidco-
vinylbenzyltriphenyl phosphonium chloride. As high as
threefold log-reduction in bacterial growth, equivalent of
99.90% reduction, is recorded against urease-active P.
mirabilis and MRSA infected artificial urine. Over two-log
decrement, corresponding to a microbial killing efficiency
of 99.37% is achieved against E. coli .
(d) The antimicrobial compositions supported the growth of
mitochondrially viable and interconnected murine
fibroblasts over 7 days in culture. The uncompromised
cytocompatibility, with respect to the medicalgrade TPU,
has been correlated to improved cell adhesion and
extensive cellular network formation, resulting from
enhanced wettability and higher surface energy of the
modified blends. Supporting information EDX analysis;
Tables: Artificial urine composition, surface energy
measurements.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could
have appeared to influence the work reported in this
paper.
Contact:
Dr Bikramjit Basu
Center for Excellence on Biomaterials,
Materials Research Center, (Prof. Bikramjit Basu's Group)
Division of Chemical Sciences,
Indian Institute of Science, Bangalore – 560012, Karnataka
bikram.iisc@gmail.com; bikram@iisc.ac.in.
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