Incorporating a broad range of
pharmaceutical- or biologics-loaded fibers into implantable medical devices
that could enable next-generation medical applications was previously not feasible
because the types of drugs capable of surviving traditional fiber manufacturing
processes were historically limited.
Pharmaceutical- and biologics-loaded
implantable textiles can result in faster healing and improved patient
compliance of medical devices. However, traditional melt extrusion processes used
to manufacture fibers destroyed the viability of all but a very limited
selection of pharmaceuticals and biologics, given the high temperatures at
which melt extrusion must occur - which often exceeds 200ºC and high shear
stress during extrusion.
Now, modified wet-extrusion processes
can occur at room temperature, eliminating the traditional temperature
limitations of pharmaceuticals and biologics that may be incorporated into
implantable medical devices and therapies with melt extrusion processes. As a
result, the range of drugs now available for controlled sustained delivery from
a fiber has been broadly expanded from those previously deliverable via
electrospun fibers, microspheres, or nanoparticles.
Using drug protection technology, the
biological activity of incorporated agents can now be preserved so that the
broadest range of pharmaceuticals and biologics ever possible remain viable when
loaded into biodegradable fibers for use in implantable devices that can
support controlled sustained delivery.
ADVANTAGES OF FIBER DELIVERY
Because fiber is both readily implantable
and maintains positional stability, it offers an unparalleled advantage when
targeting specific sites within the body. Pharmaceutical-and biologics-loaded
fiber has the ability to facilitate an entirely new and groundbreaking approach
to a variety of medical applications related to advanced drug delivery, nerve
regeneration, and tissue engineering.
The use of biodegradable fiber offers
several unique advantages over traditional pharmaceutical delivery formats,
-Longer therapeutic windows
-Targeted delivery to internal
-Controlled, sustained delivery of
pharmaceuticals and biologically based drugs
-Tailored release of multiple
pharmaceuticals from a single fiber
-Removable format if required
Fiber’s cylindrical geometry provides
a slower pharmaceutical release rate than a spherical geometry of the same
radius, resulting in an inherently longer therapeutic window for similar pharmaceutical
concentrations. Also, because fiber is both readily implantable and maintains
positional stability, it offers an unparalleled advantage when targeting
specific tissue sites, such as solid tumors. Additionally, fiber decreases the
risk to patients because fiber is removable in the rare case of an adverse
reaction, whereas microspheres and nanoparticles are delivered systemically and
typically not extractable once delivered.
EMERGENCE OF WET EXTRUSION
Traditional melt-extrusion for medical-grade
polymers occurs at temperatures that exceed the temperature tolerance of the
vast majority of pharmaceutical and biological therapeutic agents. Now, wet spinning
has emerged as a promising alternative to overcome the limitations of melt extrusion.
In the wet spinning process, a polymer
solution is injected through a spinneret into a coagulating bath. The
coagulating bath is composed of a solution that is highly miscible with the
solvent used to dissolve the polymer, yet is a non-solvent for the polymer. As
the polymer solution stream enters the coagulating bath, the solvent diffuses
from the solution stream into the coagulating bath, locally increasing the
polymer concentration. Simultaneously, the polymer stream is exposed to the non-solvent
of the coagulation bath. This combined effect causes the polymer molecules to
precipitate out of solution, forming a solid fiber.
The polymer fiber is then pulled from the
coagulation bath and taken through a number of draw stations, where the fiber is
stretched to align the polymer chains, resulting in increased tensile strength.
While these draw stations typically include ovens to heat the fiber during the
pulling process, the temperatures are typically limited to body temperature,
allowing the residual solvents (and non-solvents from the coagulating bath) to
provide the molecular mobility required to allow the polymer chains to align
and provide high mechanical properties to the fiber.
The challenge posed to retained drug viability
in traditional wet extrusion is the solvent system that enables fiber formation
itself. Exposure to the solvents and non-solvents used during extrusion may
destroy incorporated pharmaceuticals or biological agents. However, it is now
possible to protect the pharmaceutical from the solvent; enveloping it in a
protected zone within the polymer solution thereby protecting the drug from the
solvent environment. Prior to use in medical applications, however, the
solvents must be removed from the fiber. Several processes can be used to effectively
remove residual solvent to levels below the allowable limit set by FDA
guidelines while preserving the loaded drug’s viability. Wet fiber extrusion is
a very controlled process, yielding more uniform size distribution than the
distribution typically found in other formats. Multi-layered, coaxial fibers
may be readily produced with each layer containing a unique pharmaceutical and
polymer combination, thus enabling tailored release kinetics for multiple pharmaceuticals
in a single fiber.
By employing a patented extrusion process
based on the fundamentals of wet spinning, a broad range of polymers may be
loaded with viable drugs including both synthetic and biopolymers. Wet-extruded
fibers are ideal for use in current and next-generation implantable medical
devices, regenerative medicine, and as pharmaceutical depots for slow
controlled release. The localized pharmaceutical delivery capability of these
fibers enables medical device designers to orchestrate the body’s response to the
device. Depending on the choice of drug, it is possible to mitigate unwanted
reactions and promote desired responses.
NEXT GENERATION OF MEDICAL APPLICATIONS
Allowing sensitive pharmaceuticals and
biologics to remain viable when loaded into fibers enables the development of
drug delivery devices with tailored release kinetics and retained activity.
These fibers are ideal for incorporation into any number of implantable medical
device applications that benefit from the controlled release of pharmaceutical
and biological agents within the body directly to the internal sites where they
This technology has the potential to revolutionize
many medial applications, including spinal cord repair, nerve regeneration,
tumor remediation, dermal wound healing, and many more applications. Imagine
the possibilities of medical textiles becoming scaffolding for tissue
engineering and regenerative medicine applications. The scaffolding would then
deliver growth factors that can selectively direct cell migration and tissue
growth according to proper placement of fibers loaded with growth factors within
Growth factors, such as vascular
endothelial growth factor, have been successfully loaded into fibers as well.
Even virus particles have been loaded into fibers and implanted into
immune-compromised animals, resulting in efficient transfection.
The controlled release and specific drug-eluting
capabilities of wet extruded fiber-based systems are well-suited for a variety of
medical applications, including meshes and weaves for current textile
applications, sutures, ligatures, and scaffolding. In fact, the fibers are
sufficiently strong for use as a biodegradable, self-expanding, pharmaceutical-loaded
FOR MEDICAL & REGENERATIVE APPLICATIONS
Beyond the many uses in implantable medical
devices and pharmaceutical depots, drug delivery via biodegradable fibers is
poised to enable paradigm-shifting advancement in tissue engineering and regenerative
With wet extrusion, sensitive growth factors,
such as Nerve Growth Factor (NGF), Vascular Endothelial Growth Factor (VEGF),
and other sensitive biological molecules, including immune proteins and
enzymes, such as IgG and even live adenoviruses, can be loaded and delivered via
Fibers loaded with such biologics and incorporated
into implantable medical devices are ideal for a number of regenerative applications,
-Solid tumor remediation
-Spinal cord repair
-Dermal wound healing
Fiber is mechanically strong enough to
be woven, knitted, or braided to create physiologically meaningful
three-dimensional structures that can support tissue scaffolding. For example,
a fiber running through a scaffold releasing VEGF may induce angiogenesis along
its pathway, while another fiber in that same scaffold releases NGF to direct
the growth of nerve tissue along another specific pathway as defined by that
fiber. This pharmaceutical delivery technology also enables fibers with
controlled pharmaceutical concentration gradients along the length of the fiber
to encourage cell migration. These three-dimensional structures make possible
the creation of physiologically meaningful architectures through site-specific
In animal experiments, fiber has been shown,
for example, to promote peripheral nerve regeneration. A parallel array of fibers
provides excellent scaffolding for guiding neurons and fiber loaded with
biologically active neurotrophic factors has been shown to attract neurons from
isolated DRG cells in cell culture experiments.
CORD INJURY REPAIR
The central nervous system (CNS) is
biologically very different from the peripheral nervous system (PNS),
especially in terms of wound healing. In the CNS, unlike the (PNS), there is
limited regenerative capacity. Research indicates that the axons do attempt to
regenerate following injury; however, there are many roadblocks that impede functional
recovery. For example, in the myelin (a substance that wraps around many axons
to speed up electrical signal conduction) there are substances that inhibit the
growth of the axons. When the PNS is injured, the myelin is rapidly degraded by
white blood cells and Schwann cells (the type of cells that make myelin in the
PNS). In CNS injury, however, both the white blood cells and the
oligodendrocytes (the cells that make myelin in the CNS) are much less effective
at clearing the myelin rendering less effective removal of inhibitory substances.
In the PNS, Schwann cells produce large amounts of neurotrophic factors, which
is a beckoning call to the regenerating axons to induce and guide their growth.
The oligodendrocytes (CNS counterpart), however, produce much less of these
factors. Also, in the CNS, the glial cells (supportive cells in the CNS) form
“scar” tissue very rapidly following injury, called a glial scar, which
consists of growth inhibitory substances. This glial scar is highly effective
at stopping the axons from bridging even very small gaps.
Now that roadblocks to healing are better
understood, by delivering sensitive growth factors directly to the injury site,
nerve regeneration can be promoted without requiring tissue to be harvested
from elsewhere in the patient’s body for grafting. This could potentially
advance the treatment and recovery of patients with previously irreversible
spinal cord injuries resulting in paralysis.
The growth factor-loaded fiber could enable
the creation of three-dimensional concentration gradients of neurotrophic
factors that are positionally stable over time, and these gradient scaffolds
may be surgically implanted into an injured spinal cord. The concentration
gradients of the various neurotrophic factors may selectively entice motor and sensory
axons to cross a gap in opposite directions in the spinal cord by directing axonal
This approach could possibly be
indicated in spinal cord injury patients, where the spinal cord injury resulted
in a lesion, or was severed. This treatment may even apply to old injuries as
well, in which case the number of potential recipients increases significantly,
as some 250,000 people in the US are currently completely disabled due to a
previous spinal cord injury.
DIAMETER VASCULAR GRAFTS
Small-diameter vascular grafts for use
in the treatment of cardiovascular disease have proven challenging to develop
due to the need to induce successful endothelialization and, consequently, to
prevent the unwanted formation of blood clots resulting from graft
implantation. While blood clots present limited clinical harm in large vessels,
in small diameter arteries, the risk to the patient from clotting is
Grafts constructed of drug-eluting
fiber may hold the key to enabling small diameter grafts to finally become a
viable option for treating cardiovascular disease. By loading medical textiles
with the right choice of growth factors for incorporation in the small diameter
graft, complete endothelial coverage may be achievable to prevent the likelihood
of blood clot formation in the artery.
Wet-extruded fiber with drug protection
technology eliminates the traditional limitations of pharmaceuticals and
biologics that may be incorporated into implantable medical devices with melt
extrusion and provides additional benefits compared to other technologies such
as electrospun fibers, microspheres, or nanoparticles. These extrusion
processes that occur at room temperature enable loading of the widest range of
pharmaceutical and biological agents ever possible for delivery from
biodegradable implantable devices, thereby enabling localized, controlled delivery
within the body, which can facilitate breakthroughs in medical applications,
such as nerve generation, spinal cord injury repair, tissue engineering, and
even vascular grafts.
To view this issue
and all back issues online, please visit www.drug-dev.com.
Dr. Kevin Nelson earned his PhD from The
University of Texas Southwestern Medical Center at Dallas under the direction of
Dr. Robert Eberhart. As a faculty member in Biomedical Engineering at the
University of Texas at Arlington in 1996, he joined a team working on an NIH
grant to develop a fiber-based, biodegradable vascular stent with the goal of
delivering gene therapy to the vessel wall. Simultaneously working with Dr.
Nathan Schwade to develop drug-loaded microspheres for improved wound healing,
he eventually combined the drug-loading techniques of microspheres with the
fiber for the biodegradable stent, and fiber-based drug delivery was born.
Eventually patented, this technology has been the focus of Dr. Nelson’s
professional life and the driver behind TissueGen, Inc.