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European Biopharmaceutical Review

Tomorrows World

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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