8 research outputs found
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AAVR-Displaying Interfaces: Serotype-Independent Adeno-Associated Virus Capture and Local Delivery Systems.
Interfacing gene delivery vehicles with biomaterials has the potential to play a key role in diversifying gene transfer capabilities, including localized, patterned, and controlled delivery. However, strategies for modifying biomaterials to interact with delivery vectors must be redesigned whenever new delivery vehicles and applications are explored. We have developed a vector-independent biomaterial platform capable of interacting with various adeno-associated viral (AAV) serotypes. A water-soluble, cysteine-tagged, recombinant protein version of the recently discovered multi-AAV serotype receptor (AAVR), referred to as cys-AAVR, was conjugated to maleimide-displaying polycaprolactone (PCL) materials using click chemistry. The resulting cys-AAVR-PCL system bound to a broad range of therapeutically relevant AAV serotypes, thereby providing a platform capable of modulating the delivery of all AAV serotypes. Intramuscular injection of cys-AAVR-PCL microspheres with bound AAV vectors resulted in localized and sustained gene delivery as well as reduced spread to off-target organs compared to a vector solution. This cys-AAVR-PCL system is thus an effective approach for biomaterial-based AAV gene delivery for a broad range of therapeutic applications
The Promotion of Human Neural Stem Cells Adhesion Using Bioinspired Poly(norepinephrine) Nanoscale Coating
The establishment of versatile biomaterial interfaces that can facilitate cellular adhesion is crucial for elucidating the cellular processes that occur on biomaterial surfaces. Furthermore, biomaterial interfaces can provide physical or chemical cues that are capable of stimulating cellular behaviors by regulating intracellular signaling cascades. Herein, a method of creating a biomimetic functional biointerface was introduced to enhance human neural stem cell (hNSC) adhesion. The hNSC-compatible biointerface was prepared by the oxidative polymerization of the neurotransmitter norepinephrine, which generates a nanoscale organic thin layer, termed poly(norepinephrine) (pNE). Due to its adhesive property, pNE resulted in an adherent layer on various substrates, and pNE-coated biointerfaces provided a highly favorable microenvironment for hNSCs, with no observed cytotoxicity. Only a 2-hour incubation of hNSCs was required to firmly attach the stem cells, regardless of the type of substrate. Importantly, the adhesive properties of pNE interfaces led to micropatterns of cellular attachment, thereby demonstrating the ability of the interface to organize the stem cells. This highly facile surface-modification method using a biomimetic pNE thin layer can be applied to a number of suitable materials that were previously not compatible with hNSC technology
Sliding Fibers: Slidable, Injectable, and Gel-like Electrospun Nanofibers as Versatile Cell Carriers
Designing biomaterial systems that
can mimic fibrous, natural extracellular
matrix is crucial for enhancing the efficacy of various therapeutic
tools. Herein, a smart technology of three-dimensional electrospun
fibers that can be injected in a minimally invasive manner was developed.
Open surgery is currently the only route of administration of conventional
electrospun fibers into the body. Coordinating electrospun fibers
with a lubricating hydrogel produced fibrous constructs referred to
as <i>slid</i>able, <i>in</i>jectable, and <i>g</i>el-like (SLIDING) fibers. These SLIDING fibers could pass
smoothly through a catheter and fill any cavity while maintaining
their fibrous morphology. Their injectable features were derived from
their distinctive rheological characteristics, which were presumably
caused by the combinatorial effects of mobile electrospun fibers and
lubricating hydrogels. The resulting injectable fibers fostered a
highly favorable environment for human neural stem cell (hNSC) proliferation
and neurosphere formation within the fibrous structures without compromising
hNSC viability. SLIDING fibers demonstrated superior performance as
cell carriers in animal stroke models subjected to the middle cerebral
artery occlusion (MCAO) stroke model. In this model, SLIDING fiber
application extended the survival rate of administered hNSCs by blocking
microglial infiltration at the early, acute inflammatory stage. The
development of SLIDING fibers will increase the clinical significance
of fiber-based scaffolds in many biomedical fields and will broaden
their applicability
Sliding Fibers: Slidable, Injectable, and Gel-like Electrospun Nanofibers as Versatile Cell Carriers
Designing biomaterial systems that
can mimic fibrous, natural extracellular
matrix is crucial for enhancing the efficacy of various therapeutic
tools. Herein, a smart technology of three-dimensional electrospun
fibers that can be injected in a minimally invasive manner was developed.
Open surgery is currently the only route of administration of conventional
electrospun fibers into the body. Coordinating electrospun fibers
with a lubricating hydrogel produced fibrous constructs referred to
as <i>slid</i>able, <i>in</i>jectable, and <i>g</i>el-like (SLIDING) fibers. These SLIDING fibers could pass
smoothly through a catheter and fill any cavity while maintaining
their fibrous morphology. Their injectable features were derived from
their distinctive rheological characteristics, which were presumably
caused by the combinatorial effects of mobile electrospun fibers and
lubricating hydrogels. The resulting injectable fibers fostered a
highly favorable environment for human neural stem cell (hNSC) proliferation
and neurosphere formation within the fibrous structures without compromising
hNSC viability. SLIDING fibers demonstrated superior performance as
cell carriers in animal stroke models subjected to the middle cerebral
artery occlusion (MCAO) stroke model. In this model, SLIDING fiber
application extended the survival rate of administered hNSCs by blocking
microglial infiltration at the early, acute inflammatory stage. The
development of SLIDING fibers will increase the clinical significance
of fiber-based scaffolds in many biomedical fields and will broaden
their applicability
Highly Moldable Electrospun Clay-Like Fluffy Nanofibers for Three-Dimensional Scaffolds
The development of three-dimensional
polymeric systems capable of mimicking the extracellular matrix is
critical for advancing tissue engineering. To achieve these objectives,
three-dimensional fibrous scaffolds with “clay”-like
properties were successfully developed by coaxially electrospinning
polystyrene (PS) and polyÂ(ε-caprolactone) (PCL) and selective
leaching. As PS is known to be nonbiodegradable and vulnerable to
mechanical stress, PS layers present at the outer surface were removed
using a “selective leaching” process. The fibrous PCL
scaffolds that remained after the leaching step exhibited highly advantageous
characteristics as a tissue engineering scaffold, including moldability
(i.e., clay-like), flexibility, and three-dimensional structure (i.e.,
cotton-like). More so, the “clay-like” PCL fibrous scaffolds
could be shaped into any desired form, and the microenvironment within
the clay scaffolds was highly favorable for cell expansion both in
vitro and in vivo. These “electrospun-clay” scaffolds
overcome the current limitations of conventional electrospun, sheet-like
scaffolds, which are structurally inflexible. Therefore, this work
extends the scope of electrospun fibrous scaffolds toward a variety
of tissue engineering applications
Sticky “Delivering-From” Strategies Using Viral Vectors for Efficient Human Neural Stem Cell Infection by Bioinspired Catecholamines
Controlled
release of biosuprastructures, such as viruses, from surfaces has
been a challenging task in providing efficient ex vivo gene delivery.
Conventional controlled viral release approaches have demonstrated
low viral immobilization and burst release, inhibiting delivery efficiency.
Here, a highly powerful substrate-mediated viral delivery system was
designed by combining two key components that have demonstrated great
potential in the fields of gene therapy and surface chemistry, respectively:
adeno-associated viral (AAV) vectors and adhesive catecholamine surfaces.
The introduction of a nanoscale thin coating of catecholamines, polyÂ(norepinephrine)
(pNE) or polyÂ(dopamine) (pDA) to provide AAV adhesion followed by
human neural stem cell (hNSC) culture on sticky solid surfaces exhibited
unprecedented results: approximately 90% loading vs 25% (AAV_bare
surface), no burst release, sustained release at constant rates, approximately
70% infection vs 20% (AAV_bare surface), and rapid internalization.
Importantly, the sticky catecholamine-mediated AAV delivery system
successfully induced a physiological response from hNSCs, cellular
proliferation by a single-shot of AAV encoding fibroblast growth factor-2
(FGF-2), which is typically achieved by multiple treatments with expensive
FGF-2 proteins. By combining the adhesive material-independent surface
functionalization characters of pNE and pDA, this new sticky “delivering-from”
gene delivery platform will make a significant contribution to numerous
fields, including tissue engineering, gene therapy, and stem cell
therapy