A newer generation of artificial biological dermal substitute that is gaining wider acceptance for use in the clinics recently is MatriDerm®. Made up of bovine collagen and an elastin hydrolysate, this product is touted for use in a single-stage procedure. MatriDerm® was shown to be able to accommodate split thickness skin autograft safely in one step with no compromise in take on burn injuries and it seemed to be feasible for use in critically ill patientsIt was suggested that unlike IntegraTM which has antigenic properties due to the presence of chondroitin-6-sulfate, the combination of collagen and elastin in MatriDerm® can promote vascularization quicker through the support of in-growth cells and vessels while improving stability and elasticity of regenerating tissue. Furthermore, higher rate of degradation and difference in neodermal thickness of MatriDerm® compared to IntegraTM might give the former an extra edge; even though there is still relatively weak scientific evidence on their comparison in the current literature
Being the most widely accepted artificial biological dermal substitute , the use of IntegraTM which is made up of bovine collagen and chondroitin 6-sulfate, has been reported to give good aesthetic and functional outcomes when compared to using split thickness skin autograft alone . However, it is known that infection still remains the most commonly reported complication of IntegraTM . Meticulous wound bed preparation before the use of this template (or similar type of artificial biological materials) has been reported to be critical to ensure good take. Otherwise with the collection of hematomas and seromas beneath the material, the product is susceptible to infection resulting in a costly loss of an expensive tissue-engineered product and manpower time, while increasing the length of hospital stay for the patient.
Integra® Dermal Regeneration Template Single Layer "Thin"
Integra® Dermal Regeneration Template Single Layer "Thin" is the latest extension of Integra's collagen range of dermal repair products. Since the introduction of IDRT in 1996, the brand portfolio has expanded to include single layer, bilayer and flowable versions. This latest addition reinforces the company's proven advanced collagen technology for more than 20 years in a variety of indications, including life-threatening burns, scar revisions and diabetic foot ulcers.
"The European clinical community has been looking forward to the market release of Integra Single Layer Thin, the thinnest dermal substitute available," said Stéphane Corp, vice president of Tissue Technologies in Europe. "We will now be able to provide plastic and reconstructive surgeons a thinner matrix for dermal repair they can use in a single-stage procedure, while maintaining the same aesthetic and functional benefits of a two-stage procedure, which will ultimately reduce overall hospital stays for patients."
Skin tissue engineering rat racing: A coincidence?
The year 1975 seems to be a special year for skin tissue engineering, even before the term “tissue engineering” was officially adopted more than a decade later by the Washington National Science Foundation bioengineering panel meeting in 1987 [5] and later its definition elucidated further by Langer and Vacanti [6] in 1993. The beginnings of skin tissue engineering can be attributed to the pioneering work of two groups in the United States forty years ago. First, Rheinwald and Green reported the successful serial cultivation of human epidermal keratinocytes in vitro [7] in 1975 and later made possible the expansion of these cells into multiple epithelia suitable for grafting [8] from a small skin biopsy. In today’s term, the work is termed “tissue engineering of the skin epidermis”. Concurrently, Yannas, Burke and colleagues reported their maiden work on the in vitro and in vivo characterization of collagen degradation rate [9] in 1975 which we believe pave the way for the design of artificial biological dermal substitute [10], resulting in the “tissue engineering of the skin dermis”.
Another coincidence?
Interestingly, six years later in 1981, both groups independently reported the clinical use of their respective tissue-engineered substitutes for the treatment of severe and extensive burns, albeit in different approaches. O’Connor et al. reported the world’s first grafting of extensive burns with sheets of cultured epithelium (expanded from autologous epidermal cells) on two adult patients with success at the Peter Bent Brigham Hospital [11, 12]. These autologous cultured sheets (Fig. 2) termed cultured epidermal autografts (CEA) were also subsequently demonstrated to provide permanent coverage of extensive full thickness burns in another two paediatric patients [13].
Meanwhile, Burke et al. (a few months after O’Connor et al.’s report) reported the successful use of a physiologically acceptable artificial dermis in the treatment of extensive burn injuries with full thickness component on ten patients [14]. This was followed by a randomized clinical trial for major burns led by Heimbach et al. [15] on the use of this artificial dermis, now known as IntegraTM Dermal Regeneration Template. This successful multi-centre study involving eleven centres and many other studies [16, 17] might have inevitably given this dermal substitute a “gold standard” status for full thickness burns treatment [18].
While ground breaking, the work of the above two groups are still far from reaching the ultimate goal of replacing skin autografts for permanent coverage of deep dermal or full thickness wounds in extensive burns.
The holy grail of creating a fully functional tissue-engineered composite skin
As much as it is claimed that tissue-engineered skin is now a reality to treat severe and extensive burns, the fact remains that current skin substitutes available are still fraught with limitations for clinical use. This is clearly evident amongst burns or wound-care physicians that there is currently no single tissue-engineered substitute which can fully replicate the spilt-thickness skin autografts for permanent coverage of deep dermal or full thickness wounds in a one-step procedure. Indeed, clinical practice for severe burn treatments have since evolved to incorporate some of these tissue-engineered skin substitutes.
Nephrotoxicity is of increasing concern in the drug development
pipeline and the kidney proximal tubule is the primary site of renal
toxicity. Conventional preclinical renal assays, such as in vitro cell
culture and animal models, often fail to accurately model the complexity
of organ toxicity seen in drug responses due to limited functionality
or species-specific variation.
ExVive™ Human Kidney Tissue is a fully human 3D bioprinted tissue
comprised of an apical layer of polarized primary renal proximal tubule
epithelial cells (RPTECs) supported by a collagen IV-rich
tubulointerstitial interface of primary renal fibroblasts and
endothelial cells.
Tissues are printed under stringent quality controlled conditions and
are designed to model native biology and architecture in a highly
reproducible manner for optimal preservation of cellular function and
transporter activity. Epithelial cells form tight junctions and maintain
stable gamma glutamyl-transferase activity and native renal transporter
expression for multiple weeks in culture.
The cellular and architectural structure of ExVive™ Human Kidney
Tissue provides an ideal means to study the many phenotypes of
nephrotoxicity including tubular transport of xenobiotics, proteins, and
ions.
Composition and architecture enables the biochemical and histological assessment of human renal toxicity.
Tissue-like complexity supports the detection of injury, compensation, and recovery.
Physiological expression of transporters models native transport activity.
Transporter-Mediated Toxicity
Cisplatin is a widely used chemotherapeutic that is well
characterized as a nephrotoxicant with multiple modes of action. On its
path towards excretion, cisplatin is taken up by RPTECs via transporters
such as OCT2. Upon accumulation of cisplatin in the epithelial cells,
reactive oxygen species and toxic glutathione conjugates are formed
resulting in cell damage and subsequent renal toxicity. Cimetidine, an
OCT2 inhibitor, can block the accumulation of cisplatin and the ensuing
tissue damage.
Cisplatin-mediated nephrotoxicity and its prevention by cimetidine was shown in ExVive™ Human Kidney Tissue.
Tissues are treated for 7 days with increasing doses of cisplatin.
Dose-dependent decrease in overall tissue viability (Resazurin) and epithelial-specific viability (GGT) is observed.
Biomarkers for renal toxicity, Clusterin and NGAL, are detected in response to insult.
Inhibition of OCT2 by cimetidine effectively blocks cisplatin-induced toxicity.
NovoView™ Preclinical Safety Testing Services
ExVive™ 3D Bioprinted Kidney Tissues are available through our
NovoView™ Preclinical Safety Testing Services that are designed
specifically to meet your study requirements. We work closely with you
to design an optimal combination of biochemical and histological
readouts to assess the physiologically-relevant effects of your compound
on human tissues.
At Organovo, we apply state of the art quality control and assurance
processes to ensure that our customers can rely on the quality and
reproducibility of the data we generate. Our tissue team has years of
experience in every step of the bioprinting process, from bioprinting
itself to subsequent maintenance, monitoring, and analyses of the
ExVive™ Human Kidney Tissues.
Our dedicated team of scientific experts provide comprehensive consultation to determine which parameters best suit your needs.
Clinically-Relevant Answers in Three Simple Steps
Study Design
Projects are initiated by in-depth consultation with our toxicology
experts to define study design details, including time frame, dosing
regimen, and readouts. Tissue Testing
Customer-provided test articles are evaluated on ExVive™ 3D Bioprinted Tissue generated by our tissue experts. Data Evaluation
A comprehensive study report is provided, and reviewed together with Organovo scientists.
L'Oreal makes cosmetics and
hair color. It also makes skin. Human skin, created in a lab, so it can
test its products without using people or animals. Now it's talking
about printing the stuff, using 3-D bioprinters that will spit out dollops of skin into nickel-sized petri dishes.
The
idea is to produce skin more quickly and easily using what is
essentially an assembly line developed with Organovo, a San Diego
bioprinting company. Such a technique would allow the French cosmetics
company to do more accurate testing, but it also has medical
applications—particularly in burn care.
Treating severe burns typically involves grafting a healthy patch of
skin taken from elsewhere on the body. But large burns present a
problem. That has researchers at Wake Forest
experimenting with a treatment method that involves applying a small
number of healthy skin cells onto the injury and letting them grow
organically over the wound. 3-D-bioprinted skin potentially could be
produced faster, provided Organovo can successfully replicate the cell
structure of human epidermis.
L’Oreal already has a massive lab in Lyon, France, to produce its patented skin, called Episkin,
from incubated skin cells donated by surgery patients. The cells grow
in a collagen culture before being exposed to air and UV light to mimic
the effects of aging. Organovo pioneered the process of bioprinting
human tissues, most notably creating a 3-D-printed liver system.
Both parties benefit from the partnership: L’Oreal gets Organovo’s
speed and expertise, and Organovo gets funding and access to L’Oreal’s
comprehensive knowledge of skin, acquired through many years and over $1
billion in research and development.
At the moment, L'Oreal uses its epidermis samples
to predict as closely as possible how human skin will react to the
ingredients in its products. If L'Oreal can more quickly iterate on the
molecular composition of its skin samples, it can produce more accurate
results, conceivably across different skin phenotypes. That means
products like sunscreen and age-defying serums—which inevitably will
yield varying results across varying skin types—can be tweaked for
greater efficacy.L'Oreal also has a history of
selling Episkin to other cosmetic and pharmacology companies. The
company won’t disclose the going rate, but in 2011 told Bloomberg
it sold half-centimeter-wide samples for €55 each (about $78 each at
the time). That said, Guive Balooch, who runs L’Oreal’s in-house tech
incubator, says the bioprinting will be done primarily for research
purposes.
The French cosmetics giant has partnered bioprinting startup Organovo
to figure out how to 3D print living, breathing derma that can be used
to test products for toxicity and efficacy.
“We’re the first beauty company Organovo has worked with,” says Guive
Balooch, global vice president of L’Oreal’s tech incubator.
The firm is already growing more than 100,000 skin samples annually,
but under the current method, skin samples are grown from tissues
donated by plastic surgery patients in France are then cut into thin
slices and broken down into cells.
With San Diego-based Organovo’s help, L’Oreal aims to speed up and automate skin production within the next five years.
Research for the project will take place in Organovo’s labs and
L’Oreal’s new California research center. L’Oreal will provide skin
expertise and all the initial funding, while Organovo, which is already
working with such companies as Merck to print liver and kidney tissues,
will provide the technology.
Organovo has already made headlines with claims that it can 3D-print a
human liver but this is its first tie-up with the cosmetics industry.
Its statement explaining the advantage of printing skin, offered
little detail: “Our partnership will not only bring about new advanced
in vitro methods for evaluating product safety and performance, but the
potential for where this new field of technology and research can take
us is boundless.”
It also gave no timeframe for when printed samples would be available, saying it was in “early stage research”.
However, printed skin has more value in a medical scenario, potentially creating stores of spare skins for burn victims.
Dr. Marc Jeschke, the head of one of
Canada's largest burn treatment centers, had to admit the 3D skin
printer in his hands didn't look revolutionary."I actually find
it kind of fish-tanky," he told CBS News, laughing. But this boxy
prototype could change the way burns are treated, from current skin
grafting methods Jeschke calls "barbaric" to a process his team believes
will be faster, cheaper and easier on the patient, with an end result
-- functional human skin -- promising to be just like the real thing.
"It's cutting edge," said Jeschke, the director of Ross Tilley Burn Centre
at Sunnybrook Health Sciences Centre in Toronto, whose team developed
the process and printer in collaboration with researchers from the
University of Toronto. "We can mimic how your skin looks. And that's the
evolvement, that's something new, that's something novel."
To begin the process of creating new human skin
on the printer, Jeschke explained that healthy skin cells are first
harvested from the burn patient, then analyzed and multiplied in the
lab.
"We grow these cells in various containers and make them exactly into
the cell type that we want," said Jeschke. Then, "the printer tells the
cells where to go."
It does so via a cartridge, which weaves the
cells together with a gel-like matrix serving as the skin's 3D
scaffolding. The cellular tapestry that emerges from the cartridge
floats through the printer's reservoir and gathers around a rotating
drum. The strips are then collected and cultured.
"You basically imprint your various cells into this three-dimensional
matrix that comes out and it's basically ready to be put on the
patient," said Jeschke.
The printer is still in preclinical
trials, but Jeschke's team said they hope to move to human trials within
two years, and if those go well, printers like these could be in
hospitals and helping burn patients within five years.
But to get
there, Jeschke said the project will need more funding. In September,
members of the team were selected as the Canadian winners of the 2014 James Dyson Award,
a prestigious international engineering prize that comes with cash, but
only a fraction of what it will cost to get the project across the
finish line.
And there are other questions that still need to be answered.
Growing
enough cells remains a challenge. "That's the current issue, which is
how to get cells to magnify, multiply and grow in a speed that's beyond
what they normally do," Jeschke said.
Should they succeed, they'll help change a process Jeschke said is in
dire need of an upgrade. Current skin grafts for burn victims require
removing a healthy section of a patient's skin to cover their wound,
essentially creating a second wound in the process. The greater
percentage of the body that's burned, the more skin that's needed -- and
the less that's available. Skin removed for these grafts can be
expanded, but not by much.
"Your donor site, once you take the
skin, of course has to heal," explained Jeschke. "So a patient with 40
percent burn or 50 percent burn is usually in a hospital about 80 to 100
days."
With their printer, Jeschke and his team think they can
cut that recovery time down significantly. And while other methods can
leave patients with skin that doesn't match their natural color, or
lacks follicles or sweat glands, researchers on the project say their
method will allow them to eventually add those complex layers of cells.
"Someone will be able to take their own cells, and incorporate it
into this printer and have skin graft printed that are made especially
for them," said Lian Leng, a PhD student at the the University of
Toronto's Department of Mechanical Engineering and one of the lead
developers of the printer, commercially known as the PrintAlive
Bioprinter.
The printer could have a critical impact in
underdeveloped countries, where even a small burn can be fatal.
Researchers on the project plan to train doctors in Cambodia to grow cells and operate the printer themselves.
Such
a device could also provide critical support to soldiers burned on the
battlefield. That's prompting the U.S. military to fund similar
projects, like one at Wake Forest University in North Carolina.
"You
probably can reduce war fatalities significantly if you have an
off-the-shelf skin product that can be put on," said Jeschke.
Leng agreed with Jeschke's assessment of the printer's looks -- "It really is a mini version of a fish tank."
It's a fish tank, though, that could eventually save lives.
University of Toronto engineering students Arianna McAllister and Lian Leng took first prize in the Canadian leg of the 2014 James Dyson Awards program
with their PrintAlive Bioprinter, receiving a $3,500 prize and the
chance to compete internationally with teams from 18 countries for
$50,000 more. The James Dyson Foundation,
a non-profit dedicated to “encouraging young people” in the engineering
and scientific fields, uses its annual award program to feature
students’ “industrial or product designs that solve a problem.”
The problem addressed by the Toronto team is twofold: firstly, that
severe burns often cause damage to both the epidermis and the dermis
(the outer and inner skin layers, respectively), which contain different
cells and cell structures and therefore require specialized treatments.
In such cases, Leng tells CBC news,
“It’s very difficult for the body to regenerate itself.” Being able to
close these wounds quickly, she added, is paramount to preventing
fatalities. The second issue the team tackled was the need to produce
flexible, skin-like materials with 3D printers which would survive
grafting procedures; conventional 3D printers, they found, work best
with harder materials, and have been unable to structure usable skin
grafts involving complex layering of different cells needing different
environments.
With the help of Boyang Zhang, a recent PhD, Axel Guenther, an associate
professor of mechanical and industrial engineering at the University of
Toronto, and burn surgeon Dr. Marc Jeschke, the students worked to
develop a new kind of printer cartridge. Their special cartridge
contains “tiny channels filled with skin cells and the liquid
environment they require.” Prior to printing, the epidermal and dermal
cells, “along with their specialized liquid, are kept in two different
channels,” the CBC explained. During printing, each layer of artificial
skin is dispensed as a liquid into yet another liquid, which causes it
to solidify into a gel. The two solidified layers are then printed
together, one on top of the other, to generate a biodegradable dressing
containing the skin cells needed to treat deep skin wounds.
To date, the team’s 3D-printed grafts of human skin have helped
immune-compromised mice with wound healing. The team hopes to work with
larger grafts in pigs soon, and to begin human clinical trials within
two to three years. This summer, the US Army reported that its
researchers would soon begin clinical trials
to test its own skin-printing technology. It remains to be seen,
however, whether or not this Canadian team will beat them to the punch. Gizmag University of Toronto
Miniature human organs developed with a modified 3D printer are being used to test new vaccines in a lab in the US.
The
"body on a chip" project replicates human cells to print structures
which mimic the functions of the heart, liver, lung and blood vessels.
The
organs are then placed on a microchip and connected with a blood
substitute, allowing scientists to closely monitor specific treatments.
The US Department of Defense has backed the new technology with $24m (£15m).
Bioprinting,
a form of 3D printing which, in effect, creates human tissue, is not
new. Nor is the idea of culturing 3D human tissue on a microchip.
But the tests being carried out at the Wake Forest Institute for
Regenerative Medicine in North Carolina are the first to combine several
organs on the same device, which then model the human response to
chemical toxins or biologic agents.
Printing organs
The modified 3D printers, developed at Wake Forest, print human cells in hydrogel-based scaffolds.
The
lab-engineered organs are then placed on a 2in (5cm) chip and linked
together with a circulating blood substitute, similar to the type used
in trauma surgery.
The blood substitute keeps the cells alive and
can be used to introduce chemical or biologic agents, as well as
potential therapies, into the system.
Sensors which measure
real-time temperature, oxygen levels, pH and other factors feed back
information on how the organs react and - crucially - how they interact
with each other.
Dr Anthony Atala, institute director at Wake
Forest and lead investigator on the project, said the technology would
be used both to "predict the effects of chemical and biologic agents and
to test the effectiveness of potential treatments".
Printed house
Dr Atala, whose
field is regenerative medicine, said the bioprinting technology was
first used at Wake Forest for building tissues and organs for
replacement in patients.
His team had managed to replicate flat
organs, such as skin, tubular organs such as blood vessels, and even
hollow non-tubular organs like the bladder and the stomach, which have
more complex structures and functions.
But building solid organs like the heart and the liver is the hardest challenge yet.
It takes about 30 minutes just to print a miniature kidney or heart, which is the size of a small biscuit.
"There are so many cells per centimetre that making a big organ is quite complex," Dr Atala told the BBC.
But the bioprinting of full size solid organs might not be far away.
"We are working on creating solid organ implants," said Dr Atala.
Wake Forest Institute for Regenerative Medicine is leading a
unique $24 million federally funded project to develop a "body on a
chip" that will be used to model the body's response to harmful
chemical and biological agents and develop potential
treatments.
The project involves using human cells to create tiny organ-like
structures that mimic the function of the heart, liver, lung and
blood vessels. Placed on a 2-inch chip, these structures will be
connected to a system of fluid channels and sensors to provide
on-line monitoring of individual organs and the overall organ
system.
The circulating blood substitute will keep the cells alive and
can be used to introduce chemical or biologic agents, as well as
potential therapies, into the system. Hollow channels will
automatically guide the toxins or therapies that are being
evaluated from one tissue to the next and sensors will measure
real-time temperature, oxygen levels, PH and other factors.
While the
idea of culturing 3-D human tissue on a chip is not new, this will
be one of the first efforts to combine several organs in the same
device to model the human response to chemical toxins or biologic
agents.
Brigham and Women’s Hospital, Boston – micro- and nanoscale bioengineering devices for controlling cellular behavior. University of Michigan – microscale models of the body and biomolecular devices and technologies for high-throughput drug testing. The U.S. Army Edgewood Chemical Biological Center – chemical warfare agent research, development, engineering, and testing. Morgan State University – laboratory testing of cell cultures to identify the ideal blood surrogate. The Johns Hopkins Bloomberg School of Public Health – toxicity testing and identification.
Laboratory-engineered skeletal muscle is a potential therapy for
replacing diseased or damaged muscle tissue. We have developed a
computer-controlled system to build properly organized muscle
implants in the lab.
To do this, muscle cells are attached to
strands of collagen, or connective tissue. They are then subjected to
cyclic stretching ("exercise") in a bioreactor, which is a system
designed to simulate the conditions of the human body. The
pre-conditioning allows the cells to align in one direction, fuse to
form muscle bundles. Once implanted, the implants have been shown to
promote the repair of muscle damage and to build new muscle tissue.
In
this video, the process is exaggerated for demonstration purposes. The
process is actually much slower and involves less intense stretching.
Researchers Make Significant Progress in Engineering Digestive System Tissues
WINSTON-SALEM,
N.C. – July 5, 2017 -- Researchers at Wake Forest Institute for
Regenerative Medicine have reached important milestones in their quest
to engineer replacement tissue in the lab to treat digestive system conditions
– from infants born with too-short bowels to adults with inflammatory bowel
disease, colon cancer, or fecal incontinence. Reporting today in Stem
Cells Translational Medicine, the research team verified the effectiveness of lab-grown
anal sphincters to treat a large animal model for fecal incontinence, an
important step before advancing to studies in humans. And last month in Tissue
Engineering, the team reported success implanting human-engineered
intestines in rodents. “Results from both projects
are promising and exciting,” said Khalil N. Bitar, Ph.D., AGAF, senior
researcher on the projects, and professor of regenerative medicine at the
institute. “Our goal is to use a patient’s own cells to engineer replacement
tissue in the lab for devastating conditions that affect the digestive system.” Sphincter Project:
The
lab-engineered sphincters are designed to treat passive incontinence,
the involuntary discharge of stool due to a weakened ring-like muscle
known as the internal anal sphincter.
The muscle can lose function due to age or can be damaged during child
birth
and certain types of surgery, such as cancer. Current options to repair
the internal anal sphincter include grafts of skeletal muscle, injectable
silicone material or implantation of mechanical devices, all of which have high
complication rates and limited success. “The regenerative medicine
approach has a promising potential for people affected by passive fecal
incontinence,” said Bitar. “These patients face embarrassment, limited social
activities leading to depression and, because they are reluctant to report
their condition, they often suffer without help.” Bitar’s team has been
working to engineer replacement sphincters for more than 10 years. In 2011, the
team was the first to report functional, lab-grown anal sphincters bioengineered
from human cells that were implanted in immune-suppressed rodents. The current
study involved 20 rabbits with fecal incontinence. Eight animals were treated
with sphincters engineered from their own muscle and nerve cells, eight animals
were not treated and four received a “sham” surgery. The sphincters were
engineered using small biopsies from the animals’ sphincter and intestinal
tissue. From this tissue, smooth muscle and nerve cells were isolated and then
multiplied in the lab. In a ring-shaped mold, the two types of cells were
layered to build the sphincter. The entire process took about four to six
weeks. In the animals receiving the
sphincters, fecal continence was restored throughout a three month follow-up
period, compared to the other groups, which did not improve. Measurements of
sphincter pressure and tone showed that the sphincters were viable and
functional and maintained both the muscle and nerve components. Currently,
longer follow up of the implanted sphincters is close to completion with good
results. Intestine Project: The
intestine project is aimed at helping patients with intestinal failure, which
is when the small intestine malfunctions or is too short to digest food and
absorb nutrients essential to health. Patients must get nutrition through a
catheter or needle. The condition has a variety of causes. Infants can be born
with missing or dysfunctional small intestines. In adults, surgery to remove
sections of intestine due to cancer or other disease can result in a too-short
bowel. Intestinal transplant is an option, but donor tissue is in short supply
and the procedure has high mortality rates. “A major challenge in
building replacement intestine tissue in the lab is that it is the combination
of smooth muscle and nerve cells in gut tissue that moves digested food
material through the gastrointestinal tract,” said Bitar.
Through much trial and
effort, his team has learned to use the two cell types to create “sheets” of muscle
pre-wired with nerves. The sheets are then wrapped around tubular molds made of
chitosan, a natural material derived from shrimp shells. The material is
already approved by the U.S. Food and Drug Administration for certain
applications. In the current study, the
tubular structures were implanted in rats in two phases. In phase one, the
tubes were implanted in the omentum, which is fatty tissue in the lower abdomen,
for four weeks. Rich in oxygen, this tissue promoted the formation of blood
vessels to the tubes. During this phase, the muscle cells began releasing
materials that would eventually replace the scaffold as it degraded. For phase two, the bioengineered
tubular intestines were connected to the animals’ intestines, similar to an
intestine transplant. During this six-week phase, the tubes developed a
cellular lining as the body’s epithelial cells migrated to the area. The rats gained
weight and studies showed that the replacement intestine was healthy in color
and contained digested food. The researchers are excited
by the results and their next step is to test the structures in larger animals. “Our results suggest that
engineered human intestine could provide a viable treatment to lengthen the gut
for patients with gastrointestinal disorders, or patients who lose parts of
their intestines due to cancer,” said Bitar.
Financial support for the
biosphincter project included the U.S. Armed Forces, the National Institutes of
Health under the Armed Forces Institute for Regenerative Medicine (W81XWH-13-2-0052)
and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071614
and R42DK105593 to CELLF BIO LLC). Support for the intestine project came from
Wake Forest School of Medicine. Co-researchers for the biosphincter
project were: co-lead authors Jaime L. Bohl, M.D., and Elie Zakhem, Ph.D., Wake
Forest Baptist. Researchers for the intestine project were: Elie Zakhem, Ph.D.,
lead author, Riccardo Tamburrini, M.D., Giuseppe Orlando, M.D., Ph.D., and Kenneth
Koch, M.D., Wake Forest Baptist.
Skin is the body's largest organ. Loss of the skin barrier
results in fluid and heat loss and the risk of infection. The
traditional treatment for deep burns is to cover them with healthy
skin harvested from another part of the body. But in cases of
extensive burns, there often isn't enough healthy skin to
harvest.
During phase I of AFIRM, WFIRM scientists designed, built and
tested a printer designed to print skin cells onto burn wounds. The
"ink" is actually different kinds of skin cells. A scanner is used
to determine wound size and depth. Different kinds of skin cells
are found at different depths. This data guides the printer as it
applies layers of the correct type of cells to cover the wound. You
only need a patch of skin one-tenth the size of the burn to grow
enough skin cells for skin printing.
During Phase II of AFIRM, the WFIRM team will explore whether a
type of stem cell found in amniotic fluid and placenta (afterbirth)
is effective at healing wounds. The goal of the project is to bring
the technology to soldiers who need it within the next 5 years.
3-D Printing for Head and Face Injuries
Craniofacial trauma is among the most debilitating
forms of injury because of the important functional and aesthetic
roles of the face and skull. Blast injuries and injuries from high
velocity projectiles are difficult to repair with current methods
and there is a need for novel approaches to generate replacement
tissues such as bone, nerve, blood vessels, fat, and muscle. During
Phase II of AFIRM, the WFIRM team will explore printing these complex
tissue components for facial and skull reconstruction using a 3-D
printer.
Oxygen-Generating Materials
When tissues in the body are deprived of oxygen, the
irreversible process of tissue death begins. For military
personnel, this can occur when blast injuries damage blood vessels
and interrupt the blood supply to the arms or legs. But what if
there was a way to temporarily provide oxygen to muscle tissue and
keep it alive?
Institute scientists are using safe, natural chemicals that
generate oxygen in a variety of projects - from a treatment to
promote limb salvage to incorporating the particles into organ
scaffolds. With limb salvage, the particles, in the form of an
injectable gel, could potentially slow muscle death until a surgeon
could operate and restore the blood supply. The goal is to
develop a treatment that medics could carry with them - as a way to
buy time and provide a temporary burst of oxygen until a patient
could get medical treatment.
A bioprinter is essentially like a 3D printer…for the body. 3D printers
have already made waves in the beauty industry, where companies like Mink now allow you to create makeup products in any shade you dream up. Even Smashbox offered 3D-printed lipsticks last year. Now, the recent study in IOPscience
journal takes this technology to a new level: The bioprinter combines
bioinks to create skin. The bioinks don't contain any "ink" at all.
Instead, they're the cellular components of skin, like human plasma,
primary human fibroblasts, and keratinocytes. In the same way that
cartridges and ink work together to imprint images onto paper, the
bioinks are mixed in a way that results in human skin.
So far, this technology can create two types of skin tissue. The first
is just regular skin. This is formed using a stock of generic human
cells printed on a mass scale and could be used for, say, testing new
beauty products, which could make testing on animals obsolete. The other
type of skin tissue is developed with an individual’s own cells, and it
would be used therapeutically and in special cases, like as a graft for
severe burns or skin conditions. "The outer skin layer provides a
protective barrier for our bodies against the environment," explains Joshua Zeichner,
dermatologist and director of cosmetic & clinical research in
dermatology at Mount Sinai Hospital in New York City. When that outer
skin layer is either gone or not functioning properly, you’re at risk
for infection and inflammation. Enter the new, lab-made skin. And, if
you’re wondering if there’s potential for this synthetic skin to slow
signs of aging, the answer is probably. “While the new technology will
initially be applied to chronic wounds and burns, it likely will have
cosmetic applications in the future in addressing aging skin,” says
Zeichner.
What’s especially promising about this isn’t the skin itself, since
lab-made human skin isn’t exactly new. (We’re learning so much today!)
But it usually takes around three weeks to create enough skin to cover a
large wound. The bioprinter, on the other hand, makes it happen in just
35 minutes—with no sacrifice in quality. "The generated skin was very
similar to human skin and, furthermore, it was indistinguishable from
bilayered dermo-epidermal equivalents, handmade in our laboratories,"
the authors noted in the article, which is a fancy way of saying it's
just as good as any other skin graft materials they'd been using in the
past.European regulatory agencies are currently testing it to see
how safe it is for burn patients. If it’s a success, the technology
could eventually be used to create more than just skin—think organs and
other tissues. (Talk about groundbreaking.) In the meantime, we’ll just
be here, doing our best to care for the skin we do have—for now.
Scientists from the Universidad Carlos III de Madrid (UC3M), CIEMAT
(Center for Energy, Environmental and Technological Research), Hospital
General Universitario Gregorio Marañón, in collaboration with the firm
BioDan Group, have presented a prototype for a 3D bioprinter that can
create totally functional human skin. This skin is adequate for
transplanting to patients or for use in research or the testing of
cosmetic, chemical, and pharmaceutical products.
This research has recently been published in the electronic version
of the scientific journal Biofabrication. In this article, the team of
researchers has demonstrated, for the first time, that, using the new 3D
printing technology, it is possible to produce proper human skin. One
of the authors, José Luis Jorcano, professor in UC3M's department of
Bioengineering and Aerospace Engineering and head of the Mixed Unit
CIEMAT/UC3M in Biomedical Engineering, points out that this skin "can be
transplanted to patients or used in business settings to test chemical
products, cosmetics or pharmaceutical products in quantities and with
timetables and prices that are compatible with these uses."
This new human skin is one of the first living human organs created
using bioprinting to be introduced to the marketplace. It replicates the
natural structure of the skin, with a first external layer, the
epidermis with its stratum corneum, which acts as protection against the
external environment, together with another thicker, deeper layer, the
dermis. This last layer consists of fibroblasts that produce collagen,
the protein that gives elasticity and mechanical strength to the skin.
Bioinks are key to 3D bioprinting, according to the experts. When
creating skin, instead of cartridges and colored inks, injectors with
biological components are used. In the words of Juan Francisco del
Cañizo, of the Hospital General Universitario Gregorio Marañón and
Universidad Complutense de Madrid researcher. "Knowing how to mix the
biological components, in what conditions to work with them so that the
cells don't deteriorate, and how to correctly deposit the product is
critical to the system." The act of depositing these bioinks, which are
patented by CIEMAT and licensed by the BioDan Group, is controlled by a
computer, which deposits them on a print bed in an orderly manner to
then produce the skin.
The process for producing these tissues can be carried out in two
ways: to produce allogeneic skin, from a stock of cells, done on a large
scale, for industrial processes; and to create autologous skin, which
is made case by case from the patient's own cells, for therapeutic use,
such as in the treatment of severe burns. "We use only human cells and
components to produce skin that is bioactive and can generate its own
human collagen, thereby avoiding the use of the animal collagen that is
found in other methods," they note. And that is not the end of the
story, because they are also researching ways to print other human
tissues.
There are several advantages to this new technology. "This method of
bioprinting allows skin to be generated in a standardized, automated
way, and the process is less expensive than manual production," points
out Alfredo Brisac, CEO of BioDan Group, the Spanish bioengineering firm
specializing in regenerative medicine that is collaborating on this
research and commercializing this technology.
Currently, this development is in the phase of being approved by
different European regulatory agencies to guarantee that the skin that
is produced is adequate for use in transplants on burn patients and
those with other skin problems. In addition, these tissues can be used
to test pharmaceutical products, as well as cosmetics and consumer
chemical products where current regulations require testing that does
not use animals
Journal Reference:
Nieves Cubo, Marta Garcia, Juan F del Cañizo, Diego Velasco, Jose L Jorcano. 3D bioprinting of functional human skin: production and in vivo analysis. Biofabrication, 2016; 9 (1): 015006 DOI: 10.1088/1758-5090/9/1/015006
