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European Biopharmaceutical Review
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The definition of regenerative medicine, according to the US National
Institutes of Health, is the process of creating living, functional
tissues to repair or replace tissue or organ function lost due to age,
disease, damage or congenital defects (1). It is a multidisciplinary
approach comprised of biology, medicine and engineering, and includes
tissue and stem cell engineering.
Just a few years ago, advanced
technology allowed scientists to make tremendous progress towards
realising what was once predicted for tomorrow. Many of those tomorrows
are now starting to materialise. The following are examples that were
until recently seen as future issues for development (2):
● Type
1 diabetes – insulin-producing pancreatic islets regenerated in the
body or grown in the laboratory and implanted, creating the potential
for a cure for diabetes
● Stem cell therapy – tissue-engineered heart muscle to repair human hearts damaged by an event or disease
● 3D printing – technology enabling 'made-to-order' organs of almost any configuration to be cast and implanted
●
'Smart' biomaterials – materials science meets regenerative medicine,
with materials that actively participate in, and orchestrate, the
formation of functional tissue
● New approaches – revitalising
worn-out body parts, perhaps by removing the cells from an organ, and
infusing new cells that integrate into the existing matrix and restore
full functionality
● No organ donor shortage – replacing damaged or
failing organs and other human tissue through the rapidly developing
field of innovative therapies, offering a faster, more complete recovery
with significantly fewer side-effects or risk of complications
Today, significant advances have been made in all of these areas. This article explores some of the key developments.
Type 1 Diabetes
Scientists
at the Joslin Diabetes Center in Boston, US, may have found a way to
predict, and possibly prevent, complications in Type 1 diabetes (T1D),
including major problems with the cardiovascular system, kidneys, eyes
and nerves.
“Even with very good glycemic control, people with
the disease can still develop complications that impact their ability to
work and quality of life. If we could find therapies that detect these
at an early stage, people with diabetes could lead healthier, more
productive lives,” said Rohit Kulkarni, Principal Investigator in the
Section on Islet Cell and Regenerative Biology at Joslin, and Associate
Professor of Medicine at Harvard Medical School (3).
The issue
is that there is no good animal or cellular model to represent how the
human body repairs itself or malfunctions in the case of T1D. In their
study, Kulkarni et al took skin cells from patients who had diabetes for
over 50 years and reprogrammed them into induced pluripotent stem (iPS)
cells to study the disease. They then conducted a genetic analysis of
those patients who had severe complications, versus those with no or
mild complications. Genetic analysis of the iPS and skin cells showed
“remarkable differences in expression of genes and proteins [those with
severe complications versus no/mild complications],” says Dr Kulkarni
(3).
DNA Repair
The DNA damage checkpoint pathway
that monitors the DNA repair process of the body's cells was altered in
those who developed severe complications; they were prone to experience
earlier cell death than those with no or mild complications.
Further
analysis revealed there was a higher level of the RNA molecule, miR200.
“This is a very significant finding, because miR200 plays an important
role in the DNA repair process,” says Dr Kulkarni (3). When miR200
expression was reduced in iPS and skin cells in those with severe
complications, the DNA damage checkpoint pathway machinery was restored,
and DNA damage was reduced in the cells. This makes miR200 a potential
therapeutic target and possible biomarker for early detection. “We need
to figure out the exact mechanisms by which miR200 regulates the DNA
repair process, and also determine if miR200 can be detected in the
bloodstream and serve as an effective biomarker for complications.”
Stem Cell Therapy
In
the US and EU alone, there are over 1.5 million acute myocardial
infarctions (AMIs) that occur each year. The only treatment is
palliative care or restoration of myocardial function – percutaneous
coronary intervention (PCI), or thrombolytic therapy if a PCI facility
is not available, where appropriate.
For over a decade,
scientists have been conducting both basic and clinical research using
stem cells to improve myocardial function and cardiac physiology for
patients suffering from an AMI. There are many different types of stem
cells (see Table 1 on page 18 of article PDF), but a review by
Reejhsinghani et al highlighted studies showing that only
embryonic stem cells and iPS cells currently have the potential to
generate bona fide cardiomyocytes on a scale that may potentially
replace the cell numbers lost in AMI (4,5). However, the embryonic stem
cells' inherent totipotency makes them predisposed to tumour formation,
including teratomas in animal models (4). There are also ethical issues
around the use of embryonic stem cells.
Studies using bone
marrow stem cells were popular after a landmark trial published by Orlic
et al demonstrated that bone marrow cells regenerated infarcted
myocardium in mouse models (6). The transplanted cells underwent
transdifferentiation into cardiomyocytes, forming new myocardium in the
infarcted area and resulting in significant improvement in the left
ventricular ejection fraction just nine days after cell transplantation
(4).
Stem cells are either autologous (the patient's own) or
allogenic (from healthy volunteers). Some experts advocate the use of
allogenic stem cells, because they are free from both immunogenic
complications and the risks of malignancy (4). On the other hand,
autologous stem cells have limited differential potential, but are less
prone to rejection.
Latest Trials
CoreTherapix
has a clinical trial under way, the Cardio Repair European
Multi-disciplinary Initiative (CAREMI), that uses stem cell therapy,
AlloCSC-01 – designed as a reparative tool to treat patients who have
experienced an AMI – in order to reduce ischemic damage (7). AlloCSC-01
is developed by harvesting stem cells from the patient’s heart and
culturing them in vitro. These autologenic stem cells are then
reintroduced to the patient by intracoronary injections to activate
endogenous For over a decade, scientists have been conducting both basic
and clinical research using stem cells to improve myocardial function
and cardiac physiology for patients suffering from an AMI
These autologenic
stem cells are then reintroduced to the patient by intracoronary
injections to activate endogenous regenerative pathways, reducing
scarring and inflammation while promoting growth of new contractile
myocytes. CAREMI is currently in Phase 2 trials, with 55 patients across
eight locations in Spain and Belgium (7). The trial enrolment is
expected to be completed by the end of this quarter (only 60% of the
target number of patients have been enrolled so far), with a six-month
interim efficacy analysis due be released in the second half of 2016.
CAREMI is currently in Phase 2 trials,
with 55 patients across eight locations in Spain and Belgium (7). The
trial enrolment is expected to be completed by the end of this quarter
(only 60% of the target number of patients have been enrolled so far),
with a six-month interim efficacy analysis due be released in the second
half of 2016.
In another development, CardioCell is using
allogenic stem cells derived from the bone marrow of healthy volunteers
and, more specifically, ischemia-tolerant mesenchymal stem cells
(itMSCs) in stem cell treatment (8). These cells work primarily on the
environment for healing. Circulating throughout the body and homing to
sites of injury, they reportedly release growth factors into the damaged
tissue, rescuing affected cells from death and creating the right
conditions for the newly mobilised cells to proliferate and repair.
The
company currently has two AMI clinical trials ongoing with itMSCs: a
Phase 2a ongoing double-blinded, multi-centre, randomised study to
assess the safety, tolerability and preliminary efficacy of a single
intravenous dose of allogenic mesenchymal bone marrow cells to subjects
with ST segment elevation myocardial infarction in the US; and a Phase 3
intravenous administration of its MSCs for AMI patients in Kazakhstan.
There
is still a debate as to which type of stem cell to use and which
therapy – autologenic or allogenic – will produce better results. Time
will tell once the results of the clinical trials are announced.
3D Printing of Organs
The
idea that every household should own a 3D printer, to create anything
from household appliances to evening attire, is gaining momemtum. 3D
printing has exploded onto the scene in the last couple of years, as the
technology has become progressively less expensive.
This
technology has rapidly expanded into the medical field, where physicians
are currently using 3D printing to generate human organs destined for
planning surgical procedures, or for creating custom scoliosis braces,
trachea tubes and even prosthetics, including eyes.
Scientists
have also used stem cells and 3D printing to make miniature blood
vessels in Germany (see Figure 1 on page 19 of article PDF), human kidneys in China and
livers in the US (9-11). Although these organs have only survived for a
few hours or days, the fact there has been success in printing live
organs is truly groundbreaking.
The ultimate goal is organ
transplant and eliminating the donor organ shortage. In this scenario,
if a patient needed a new organ, physicians and scientists would use the
patient's own stem cells to print the organ, transplant it into the
patient, and not be concerned with rejection. There would no longer be a
waiting list for organs, nor a black market for the trading of human
organs, since they would be readily available at all times. However,
while we are waiting for scientists to perfect the printing of human
organs, companies such as Organovo, which produced the first miniature
human liver, are currently utilising these livers and other human
tissues for drug testing, research and drug discovery applications by
pharmaceutical companies and academic research organisations.
Smart Biomaterials
These
are defined as "biomaterials that allow for the gradual endogenous
remodelling of native tissue leading to the replacement of implant
material, manufactured to replace a missing biological structure, with
fully functional ECM [extracellular matrix] and cells that existed at
the implant site prior to damage" (12). In summary, the biomaterial
interacts and promotes tissue regeneration with native tissues and then
slowly gets absorbed by the body as it is being replaced by native
tissue.
Another definition is the use of genes within the body
to control the regeneration process, and novel biomaterials that are
gene-activated, where the tissue repair process can be specific for an
individual and the disease (13). Researchers must design implant
materials that mimic the natural ECM that not only supports cellular
structure, but also functions just as well, regulating growth, cell
migration, differentiation, and so forth.
Engineering Hurdles
This
type of tissue engineering has many challenges. Since the biomaterial
must interact with and influence cell behaviour and performance,
scientists are trying to develop bioactive materials by incorporating
signalling molecules (neurotransmitters, cytokines and growth factors)
into the scaffolding (12). Other engineering hurdles (12), although not
exclusive to the development of smart biomaterials, include:
● Stimulating the body to maintain its natural ability for new blood vessel formation
●
Providing an environment within the engineered biomaterial to support
cellular proliferation and survival – a hallmark of functional tissue
● Regenerating neurons
● Bone formation in vitro
Needless to say, these are very complex tasks, and discussion of possible solutions are beyond the scope of this article.
Humacyte
is making progress with blood vessels. The company is taking human
cells and growing them as a scaffold in the shape of a tube (14). When
the scaffold or ECM is formed, the human cells are washed away to reduce
the risk of rejection; the scaffold is then implanted, allowing the
patient's own tissue to grow into the vein. The technology was developed
by Duke University, and they are planning to start Phase 3 clinical
trials.
Intriguing Possibilities
Revitalising
worn-out body parts will likely come to fruition once the tissue
engineering challenges are solved. Solutions may not unfold in quite the
way it was foreseen a few years ago but, when we are able to help the
body to regenerate damaged tissue with the help of bioactive materials,
the outcomes would be the same. Likewise, 3D printing of organs,
although not technically self-regeneration, can certainly be considered
revitalisation.
Scientists have made remarkable advances in
technology and regenerative medicine. No one could have predicted 20
years ago that today we would be able to 3D print anything, especially
human organs. At the same time, significant developments in tissue
engineering, stem cell therapy and gene editing offer intriguing
possibilities for the future of medicine and healthcare. With further
help from science, we may not be that far from being able to regenerate
organs, limbs or other body parts.
References
1. NIH
Fact Sheet: Regenerative Medicine, Yesterday, Today & Tomorrow, NIH
Research Timelines. Visit: www.report.nih.gov/
NIHfactsheets/ViewFactSheet.aspx?csid=62&key=R
2. NIH Report:
Yesterday, Today & Tomorrow, NIH Research Timelines, Visit:
www.report.nih.gov/NIHfactsheets/ ViewFactSheet.aspx?csid=62&key=R
3.
New discovery provides insight into the development of complications in
Type 1 Diabetes, Joslin Diabetes Center, 4 August 2015. Visit:
www.joslin.org/news/new-discoveryprovides-insight-into-complications-in-type-1-diabetes.html
4. Reejhsinghani R, Han-Jen Shih H and Lotf AS, Stem cell therapy in acute myocardial infarction, J Clin Exp Cardiology S:11, 2012. Visit: www.omicsonline.org/stem-cell-therapy-in-acutemyocardial- infarction-2155-9880.S11-004.pdf
5. Mummery CL, Davis RP and Krieger JE, Challenges in using stem cells for cardiac repair, Sci Transl Med 2(27), 2010. Visit: www.ncbi.nlm.nih.gov/pubmed/20393186
6. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM et al, Bone marrow cells regenerate infarcted myocardium, Nature 410: pp701-705, 2001. Visit: www.ncbi.nlm.nih.gov/pubmed/11287958
7.
Heart Attacks: TiGenix advances its cardiac stem-cell therapy, 9
September 2015. Visit:
http://labiotech.eu/heart-attacks-phasei-results-of-e11-3m-eu-supported-stem-cell-therapy
8. CardioCell, Our stem cells. Visit: http://stemcardiocell.com/technology/our-stem-cells
9.
Blood vessels from your printer, Fraunhofer-Gesellschaft press release,
Fraunhofer Institute, 13 September 2011. Visit:
www.igb.fraunhofer.de/en/press-media/pressreleases/2011/blood-vesselsfromyour-printer.html
10. China View: Living kidneys 3D printed in China, Medical Design
Technology, 9 September 2013. Visit:
www.mdtmag.com/videos/2013/09/living-kidneys-3dprinted-china
11.
Fienberg A, Scientists have 3D-printed mini human livers for the first
time ever, Gizmodo, 23 April 2013. Visit: http://gizmodo.com/5995271/scientists-have-3d+printed-mini-human-liversforthe-
first-time-ever
12. Mieszawskac AJ and Kaplan DL, Smart biomaterials – regulating cell behavior through signaling molecules, BMC Biol 8(59), 2010. Visit: www.ncbi.nlm.nih.gov/pmc/articles/PMC2873335
13.
Brenda Collins, Smart Biomaterials: healing thyself, Examiner.com, July
29, 2010. Visit:
www.examiner.com/article/smart-biomaterials-healing-thyself
14. Vinluan F, Humacyte lands $150m Series B for Phase 3 study of lab-grown veins, Xconomy,
20 October 2015. Visit:
www.xconomy.com/raleigh-durham/2015/10/20/humacyte-lands-150m-series-b-for-phase-3-studyof-lab-grown-veins/?utm_source=xconomy&utm_
campaign=6e75c68530-newsletter_exome&utm_
medium=email&utm_term=0_2aa91c0bc9-6e75c68530-288454541
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