Global Stem Cells Group Announces Opening of New Research Facility at Marmara University’s Main Campus in Istanbul, Turkey
Collaboration Set to Propel Regenerative Medicine Research and Innovation
Miami, May 20, 2023 – Global Stem Cells Group, a leading provider of regenerative medicine solutions, is thrilled to announce the opening of its state-of-the-art research facility at Marmara University’s Main Campus in Istanbul, Turkey. This collaborative endeavor between Global Stem Cells Group, ReGen (described below), and Marmara University aims to advance research and knowledge in the fields of neurological conditions, autoimmune diseases, and the validation of safety and efficacy of procedures and Cellgenic products.
ReGen, a globally recognized network of clinics and a commercial partner of Global Stem Cells Group, is dedicated to providing cutting-edge cellular therapies that enhance patient well-being. This joint effort between ReGen, Global Stem Cells Group, and Marmara University seeks to drive research and innovation in cell therapy and tissue engineering.
Renowned for its commitment to excellence in education, research, and innovation, Marmara University provides an exceptional foundation for Global Stem Cells Group’s new research facility. With a strong emphasis on interdisciplinary collaboration and forefront research, Marmara University has emerged as a hub of intellectual discovery and academic achievement. The University’s renowned faculty and state-of-the-art infrastructure make it an ideal partner for Global Stem Cells Group in driving advancements in regenerative medicine.
By establishing this collaborative research facility at Marmara University, Global Stem Cells Group plans to access to the university’s wealth of expertise and resources, enabling the organization to undertake extensive clinical studies and groundbreaking research. Together, they will focus on addressing the challenges posed by neurodegenerative diseases and other medical conditions, aiming to develop innovative treatments and therapies that can significantly improve patient outcomes.
“Both Global Stem Cell Group and its commercial partner, ReGen, are thrilled to establish our new research facility in partnership with Marmara University.” Benito Novas, CEO of Global Stem Cells Group, expressed his enthusiasm for the collaboration. “This collaboration holds significant meaning for us, particularly in terms of the Cellgenic brand,” he added.
The Cellgenic product line encompasses a range of point-of-care regenerative medicine products, including autologous and allogeneic therapies, as well as exosomes. After examining the independent testing and validation of these products employed by Marmara University, Global Stem Cell Group is confident in the University’s quality and effectiveness.
The newly inaugurated research facility is expected to serve as a hub for extensive clinical studies on various medical conditions, with a particular focus on neurodegenerative diseases and ailments treatable through cell therapy and tissue engineering. This research is expected to contribute to the advancement of medical knowledge and the development of innovative treatments that have the potential to transform the lives of patients worldwide.
Global Stem Cells Group and its commercial partner, ReGen, extend their gratitude to Marmara University for its unwavering commitment to advancing regenerative medicine research and innovation. The collaboration between Global Stem Cells Group, ReGen, and Marmara University signifies what the parties believe is a significant milestone in the field of regenerative medicine, combining the expertise and resources of three leading institutions to drive breakthrough discoveries and shape the future of healthcare.
For more information about Global Stem Cells Group and its regenerative medicine solutions, please visit https://www.stemcellsgroup.com/.
About Global Stem Cells Group
Global Stem Cells Group is a leading provider of regenerative medicine solutions, dedicated to advancing healthcare through innovative therapies. With a global presence and a multidisciplinary team of experts, the organization strives to harness the potential of stem cells and regenerative medicine to improve patient outcomes across various medical fields. Through its extensive network of clinics, research facilities, and training centers, Global Stem Cells Group is committed to pushing the boundaries of regenerative medicine and making a positive impact on global healthcare.
About ReGen
ReGen is a renowned network of clinics and commercial partner of Global Stem Cells Group worldwide, offers cutting-edge cellular therapies to enhance the well-being of its patients. ReGen aims to drive research and innovation in cell therapy and tissue engineering together with Global Stem Cells Group and Marmara University.
About Marmara University
Marmara University is a prestigious educational institution renowned for its commitment to excellence in education, research, and innovation. With a strong emphasis on interdisciplinary collaboration and cutting-edge research, Marmara University has emerged as a hub of intellectual discovery and academic achievement. The university’s renowned faculty and state-of-the-art infrastructure make it an ideal partner for Global Stem Cells Group in driving advancements in regenerative medicine.
Safe Harbor Statement: Statements in this news release may be “forward-looking statements”. Forward-looking statements include, but are not limited to, statements that express our intentions, beliefs, expectations, strategies, predictions, or any other information relating to our future activities or other future events or conditions. These statements are based on current expectations, estimates, and projections about our business based partly on assumptions made by management. These statements are not guarantees of future performance and involve risks, uncertainties, and assumptions that are difficult to predict. Therefore, actual outcomes and results may and are likely to differ materially from what is expressed or forecasted in forward-looking statements due to numerous factors. Any forward-looking statements speak only as of the date of this news release, and The Global Stem Cells Group undertakes no obligation to update any forward-looking statement to reflect events or circumstances after the date of this news release. This press release does not constitute a public offer of any securities for sale. Any securities offered privately will not be or have not been registered under the Act and may not be offered or sold in the United States absent registration or an applicable exemption from registration requirements.
- Published in Press Releases
International Society for Stem Cell Application (ISSCA) and Marmara University Launch Stem Cell and Regenerative Medicine Fellowship Program in Turkey
Participants in the program will have access to over 200 hours of valuable online content and hands-on laboratory practice in the state-of-the-art facilities at Marmara University and StemBio. Generally, the program will cover a series of topics related to the general principles of regenerative medicine, including:
- Stem cell biology;
- Evidence-based treatments; and
- Tissue engineering.
Hear from Certified and Established Industry Leaders
The Stem Cell and Regenerative Medicine Fellowship Program aims to provide attendees with the chance to meet, interact, and learn from ISSCA-certified doctors, scientists, experts, and Marmara University professors with in-depth expertise in the field. There will be seven days of in-person training and a comprehensive digital course offering practical experience in stem cell classifications and laboratory applications, with a high emphasis on Good Manufacturing Practice (GMP) guidelines.
Learn About the Best Stem-Cell Application Practices and Procedures in Clinical and Manufacturing Operations
By attending the program, participants should be able to gain valuable answers to the “how to” questions related to the practical applications of stem cell biology and regenerative medicine in research laboratories and manufacturing facilities. Attendees can expect to learn the following:
- How to culture stem cells;
- How to meet quality control standards;
- How to comply with cGMP functions;
- How to operate within the recommended clinical procedures;
- How to apply and implement the regulations for stem cell processing in a certified manufacturing facility; and
- How to apply clinical guidelines and regulatory policies when developing a GMP facility
Besides, the seven-day fellowship program will also offer participants resources to bolster their stem cell operations, including copies of presentations, procedural guidelines, and all forms and documentation related to a GMP facility.
Moreover, the Stem Cell and Regenerative Medicine Fellowship Program will cover a range of clinical procedures, including:
- Tissue processing;
- Isolation of mesenchymal stem cells;
- Culture, Expansion and cryopreservation; and
- Clinical Application of stem cells for wide-ranging indications: participants will get case books and complete protocols for about 30 indications.
Why Attend the Stem Cell and Regenerative Medicine Fellowship Program?
The program provides a learning experience for medical professionals and scientists who’d love to further their knowledge and skills in stem cells and regenerative medicine. Attendees will get the opportunity to learn from the top professionals in the field and gain practical hands-on experience in world-class laboratory facilities.
Here’s what Global Stem Cells Global’s CEO, Benito Novas, had to say: “We are delighted to hold the Stem Cells and Regenerative Medicine Fellowship Program, which is designed to provide participants with the opportunity to gain and further their knowledge in stem cell biology and tissue engineering. In addition, ISSCA’s partnership with Marmara University will ensure attendees have access to professors with deep knowledge in the field and practical training in stem cell and regenerative medicine.”
For more information on the Stem Cell and Regenerative Fellowship Program, visit the ISSCA website or contact Global Stem Cells Group.
About Marmara University
Marmara University is a leading research university nestled in Istanbul, Turkey. It’s a distinguished academic institution with high authority in scientific research and academic excellence, specifically in medicine. The university provides undergraduate, graduate, and doctorate degrees, as well as certificate programs. Marmara University also boasts state-of-the-art facilities and dedicated faculty that chronicle its dedication to giving scholars world-class learning experiences and contributing to the advancement of knowledge in wide-ranging fields.
About ISSCA:
The International Society for Stem Cell Application (ISSCA) is a multidisciplinary community of scientists and physicians who aspire to treat diseases and lessen human suffering through advances in science, technology, and the practice of regenerative medicine. ISSCA serves its members through advancements made in the specialty of regenerative medicine.
The mission of the International Stem Cell Certification Agency (ISSCA) is to establish itself as a global leader in regenerative medicine certification, education, research, and training.
ISSCA provides certification training in cities worldwide because it recognizes the importance of standards and certifications in regenerative medicine as a medical specialty. To help more people, both locally and globally, as the demand for more doctors interested in and comfortable with regenerative medicine surges. ISSCA’s mission is to advance quality and uniformity in regenerative medicine worldwide.
About Global Stem Cells Group:
The Global Stem Cell Group is a family of several companies focused on stem cell medicine and research. The company uses its network to bring leadership in regenerative medicine training, research, and patient applications.
GSCG’s mission is to allow physicians to present the benefits of stem cell medicine to patients worldwide. The company also partners with policymakers, educators, and regulators to promote regenerative medicine.
Global Stem Cells Group is a publicly traded company operating under the symbol MSSV. https://finance.yahoo.com/quote/mssv/
To learn more about Global Stem Cells Group, Inc.’s companies visit our website www.stemcellsgroup.com or call +1 305 560 5331
Safe Harbor Statement:
Statements in this news release may be “forward-looking statements”. Forward-looking statements include, but are not limited to, statements that express our intentions, beliefs, expectations, strategies, predictions, or any other information relating to our future activities or other future events or conditions. These statements are based on current expectations, estimates, and projections about our business based partly on assumptions made by management. These statements are not guarantees of future performance and involve risks, uncertainties, and assumptions that are difficult to predict. Therefore, actual outcomes and results may and are likely to differ materially from what is expressed or forecasted in forward-looking statements due to numerous factors. Any forward-looking statements speak only as of the date of this news release, and The Global Stem Cells Group undertakes no obligation to update any forward-looking statement to reflect events or circumstances after the date of this news release. This press release does not constitute a public offer of any securities for sale. Any securities offered privately will not be or have not been registered under the Act and may not be offered or sold in the United States absent registration or an applicable exemption from registration requirements.
- Published in Press Releases
ISSCA’s On-site Training in Portugal
MIAMI, Florida, January 23, 2023 – The Global Stem Cells Group (GSCG) announces its long-awaited hands-on training this March 9th, 10th & 11th, 2023
The GSCG, through its International Society for Stem Cell Application (ISSCA) division, is holding a personalized, hands-on training course at Regenera clinic, located in Oeiras, Lisboa, Portugal. Industry-leading instructors across the regenerative medicine field will lead this onsite training course. We believe this course is a Total Solution for clinics as ISSCA teams will teach and train doctors and caregivers on the recent advances in regenerative medicine and cellular-based treatments.
Lisboa’s First On-site Training
Benito Novas, CEO of Global Stem Cells Group and Vice President of ISSCA, notes that “regenerative medicine is the future of health and beauty industries as more research is conducted and products developed for doctors to offer a superior service.”
Benito adds, “the training course will take a highly visual format with global experts interacting with trainees and live patients used to teach about different stem cell reintegration and procedural techniques with locally available tools and facilities.
The Lisboa training is the first in the country to bring clinics into the fold of regenerative medicine and stem cell treatments. Regenera clinic will be the first to be ISSCA certified and apply cellular therapies and regenerative medicine. Dr. Roni Lara Moya will be appointed Portugal Chapter director on 9th March.
The course design considers the needs of local trainees using a thorough scheduling process. Initial consultations between the trainees and ISSCA will inform equipment and kits availability, materials, underlying costs, and any other needs to be met during the main event.
What is the On-site Training About?
The following are some of the areas the onsite-training course will focus on:
1. Learning from Experts
A panel of stem cell therapy and regenerative medicine experts will lead the one-on-one training sessions. Cell therapy, skin regeneration techniques, bone marrow extraction, tissue engineering, and many more applications of advanced technologies to advance personalized health will be practically illustrated.
2. Trainees-Centered Treatment Protocols
The training course is personalized to every doctor and clinician’s specialization and the illness they are targeting. For example, stem cell treatment sessions will include various reintegration methods based on patients’ medical history and condition. The trainees will also have a first-hand view of how technology pushes the boundaries of regenerative medicine from research to the derivation of cell lines and, as we are all working to the possible future of genetic alteration.
Local nurses and medical assistants will also have a chance to be part of the process by going through a fully skilled procedural session that improves their assistance to the doctors.
3. International Certification
As an acclaimed stakeholder in regenerative medicine and stem cell treatment, ISSCA offers globally recognized certification to doctors and practitioners, highlighting their fascinating journey in this highly demanded field. According to the appointed chapter director of Portugal, Dr. Roni Lara Moya- “the upcoming onsite training is one of its kind ever conducted in the country. Dr. Moya asserts that “the collaboration between ISSCA and Regenerative Biomedicine Regenerative Clinic stems from a growing demand for new technologies and cutting-edge treatments that support patients’ positive health outcomes.”
4. Trends in Regenerative & Stem Cell Treatment
The training will cover stem cell and regenerative medicine’s practical, legal, technical, and ethical aspects. Laws, technological developments, and ethical concerns will be a critical part of the training course.
All are welcome to share the fantastic excitement of stem cell science and its promising future.
About ISSCA:
The International Society for Stem Cell Application (ISSCA) is a multidisciplinary community of scientists and physicians who aspire to treat diseases and lessen human suffering through advances in science, technology, and the practice of regenerative medicine. ISSCA serves its members through advancements made in the specialty of regenerative medicine.
The mission of the International Stem Cell Certification Agency (ISSCA) is to establish itself as a global leader in regenerative medicine certification, education, research, and training.
ISSCA provides certification training in cities worldwide because it recognizes the importance of standards and certifications in regenerative medicine as a medical specialty. To help more people, both locally and globally, as the demand for more doctors interested in and comfortable with regenerative medicine surges. ISSCA’s mission is to advance quality and uniformity in regenerative medicine worldwide.
About Global Stem Cells Group:
The Global Stem Cell Group is a family of several companies focused on stem cell medicine and research. The company uses its network to bring leadership in regenerative medicine training, research, and patient applications.
GSCG’s mission is to allow physicians to present the benefits of stem cell medicine to patients worldwide. The company also partners with policymakers, educators, and regulators to promote regenerative medicine.
Global Stem Cells Group is a publicly traded company operating under the symbol MSSV. https://finance.yahoo.com/quote/mssv/
To learn more about Global Stem Cells Group, Inc.’s companies visit our website www.stemcellsgroup.com or call +1 305 560 5331
Safe Harbor Statement: Statements in this news release may be “forward-looking statements”. Forward-looking statements include, but are not limited to, statements that express our intentions, beliefs, expectations, strategies, predictions, or any other information relating to our future activities or other future events or conditions. These statements are based on current expectations, estimates, and projections about our business based partly on assumptions made by management. These statements are not guarantees of future performance and involve risks, uncertainties, and assumptions that are difficult to predict. Therefore, actual outcomes and results may and are likely to differ materially from what is expressed or forecasted in forward-looking statements due to numerous factors. Any forward-looking statements speak only as of the date of this news release, and The Global Stem Cells Group undertakes no obligation to update any forward-looking statement to reflect events or circumstances after the date of this news release. This press release does not constitute a public offer of any securities for sale. Any securities offered privately will not be or have not been registered under the Act and may not be offered or sold in the United States absent registration or an applicable exemption from registration requirements.
- Published in Press Releases
ISSCA to sponsor International Congress on Advanced Therapies in Medicine in Riviera Nayarit, Mexico Nov. 24-25, 2018
ISSCA will sponsor the 6th annual International Congress on Advanced Therapies in Medicine Nov. 24-25, 2018 in Riviera Nayarit.
MIAMI, July 27, 2018—For the third consecutive year the International Association for Stem Cell Application (ISSCA) will sponsor the International Congress on Advanced Therapies in Medicine 2018 on Puerto Vallarta, Mexico.
The event will feature a commercial expo with 20 with 20 booths exhibiting new products and information for physicians in the field of regenerative medicine. More than 250 physicians are expected to be in attendance.
ISSCA will present information on its Fellowship in Cell Therapy and Tissue Engineering program, a 6-day course during which a group of experienced academicians involved in stem cell transplantation present the general principles and practice of stem cell biology and evidence-based treatments to physicians looking to optimize the treatment options that benefit the health of their patients. The fellowship program will be held in Korea Oct. 22-27, 2018.
Fellowship participants will take part in a detailed program offering hands-on experience in stem cell applications and learn cell culture protocols including plating, trypsinization, harvesting, and cryopreservation, as well as an understanding and application of quality control tests including cell count, viability, flow cytometry, endotoxin, mycoplasma and sterility.
In addition, physicians participating in the ISSCA fellowship program will learn how to perform cGMP functions including cleanroom maintenance, gowning and environmental monitoring, while gaining insight on relevant applications of stem cell processing and regulations in a certified facility. ISSCA provides fellowship attendees with the tools necessary to implement regulatory and clinical guidelines when setting up a GMP facility, as well as copies of presentations, procedural protocols and all forms associated with a GMP facility provided.
Participating physicians learn to perform clinical procedures including lipoaspirate and bone marrow isolation, and reintroducing stem cells for various indications. Case books and full protocols for approximately 30 indications are also provided.
In addition, Global Stem Cells Group )GSCG) will present its stem cell processing center, a complete solution for providers to equip their practice facilities with an on-site regenerative medicine lab. Used for tissue processing, isolation, culturing and cryopreservation of stem cells, the stem cell processing center is designed to execute a state-of-the-art stem cell laboratory using the latest technology.
GSCG provides participating regenerative medicine teams with specialized training to implement high-level processes and therapies using the stem cell processing center for better clinical interpretation, better results while maintaining compliance with safety regulations and international standards.
GSCG’s stem cell laboratory solution represents a tremendous competitive advantage and differentiator that arms regenerative medicine practitioners with the ability to perform highly advanced stem cell procedures in their facilities.
The 2018 International Congress on Advanced Therapies in Medicine in Riviera Nayarit, Mexico will be held at the Hotel Krystal Grand in Nuevo Puerto Vallarta,
For more information and to register, email info@stemcellsgroup.com, or call +1305 560 5337.
About ISSCA:
The International Society for Stem Cell Application (ISSCA) is a multidisciplinary community of scientists and physicians, all of whom aspire to treat diseases and lessen human suffering through advances in science, technology and the practice of regenerative medicine.
ISSCA serves its members through advancements made in the specialty of regenerative medicine.ISSCA’s vision is to take a leadership position in promoting excellence and setting standards in the regenerative medicine fields of publication, research, education, training, and certification.
As a medical specialty, regenerative medicine standards and certifications are essential, which is why ISSCA offers certification training in cities all over the world. The goal is to encourage more physicians to practice regenerative medicine and make it available to benefit patients both nationally and globally. Incorporated under the Republic of Korea as a non-profit entity, the ISSCA is focused on promoting excellence and standards in the field of regenerative medicine.
About Global Stem Cells Group:
Global Stem Cells Group (GSCG) is a worldwide network that combines seven major medical corporations. Each corporation is focused on furthering scientific and technological advancements in cutting-edge stem cell research, development, treatment, and training. The united efforts of GSCG’s affiliate companies provide medical practitioners with a one-stopepicenter for stem cell solutions that adhere to the highest medical standards.
Global stem cell’s mission is to be the largest recognized stem cell and regenerative medicine network in the world.
advanced therapies international congress
- Published in Press Releases
ISSCA announces fellowship in cell therapy and tissue engineering
As part of its ongoing efforts to meet growing demand among physicians for continuing education opportunities in advanced cell therapies and tissue banking, the International Society for Stem Cell Application (ISSCA) will hold its next Cell Therapy and Tissue Engineering Fellowship program in Seoul, Korea October 22 – 27, 2018.
ISSCA’s fellowship training program offers physicians an opportunity to build knowledge and increase their therapeutic skills by learning to employ new developments in tissue banking practices and advanced cellular therapies to utilize in their practices.
The fellowship training will enable participating physicians to improve their core skills and competencies in regenerative medicine, establish optimal protocols, policies, and practices in tissue, cell, and advanced therapies, and ultimately enable them to deliver superior services to their patients.
Participating physicians will have the advantage of active engagement with world-class cellular and tissue banking experts in an immersive, hands-on experience while learning theoretical and analytic methods. Fellowship mentors are seasoned professionals devoted to creating new medical technologies and laboratory applications in one of the most rapidly-growing areas of biomedical engineering.
Cell therapy and tissue engineering offer tremendous potential for a career as a practitioner or researcher. Today’s students can be tomorrow’s pioneers in improving the efficacy of medical treatments and advancing the healthcare industry.
Engineering human tissues and organs can provide new treatments and cures for diseases, including blood vessels, bone, cartilage, liver, pancreas, peripheral nerves, and skin cells. Cell therapies and tissue engineering have the potential to revolutionize disease remediation and tissue repair in miraculous ways.
Fellowship participants will have complete access to ISSCA’s accredited stem cell advanced lab protocols. The ISSCA Fellowship program is a 6-day program that offers a certificate of completion issued by ISSCA and Westminster International University in Seoul. Students who complete the fellowship become members of the ISSCA’s international network of regenerative medical professionals and standard setters, with access to events, resources, training, and support moving forward.
ISSCA is the only organization that provides a complete cell therapy and tissue engineering fellowship focused on regenerative medicine. It is also the only fellowship of its kind supported by Korean Universities.
To learn more about the ISSCA fellowship and to reserve a spot at the October 2018 program in Korea, visit the Fellowship in Cell Therapy and Tissue Engineering website, email info@stemcellsgroup.com, or call +1 813 510 9403
About ISSCA:
The International Society for Stem Cell Application (ISSCA) is a multidisciplinary community of scientists and physicians, all of whom aspire to treat diseases and lessen human suffering through advances in science, technology and the practice of regenerative medicine. ISSCA serves its members through advancements made in the specialty of regenerative medicine.
The ISSCA’s vision is to take a leadership position in promoting excellence and setting standards in the regenerative medicine fields of publication, research, education, training, and certification.
As a medical specialty, regenerative medicine standards and certifications are essential, which is why ISSCA offers certification training in cities all over the world. The goal is to encourage more physicians to practice regenerative medicine and make it available to benefit patients both nationally and globally. Incorporated under the Republic of Korea as a non-profit entity, the ISSCA is focused on promoting excellence and standards in the field of regenerative medicine.
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cell therapy fellowship
- Published in Press Releases
Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise
Although the clinical demand for bioengineered blood vessels continues to rise, current options for vascular conduits remain limited. The synergistic combination of emerging advances in tissue fabrication and stem cell engineering promises new strategies for engineering autologous blood vessels that recapitulate not only the mechanical properties of native vessels but also their biological function. Here we explore recent bioengineering advances in creating functional blood macro and microvessels, particularly featuring stem cells as a seed source. We also highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology.
Ischemic diseases, such as atherosclerotic cardiovascular disease (CVD), remain one of the leading causes of mortality and morbidity across the world (GBD 2015 Mortality and Causes of Death Collaborators, 2016, Mozaffarian et al., 2016). These diseases have resulted in an ever-persistent demand for vascular conduits to reconstruct or bypass vascular occlusions and aneurysms. Synthetic grafts for replacing occluded arterial vessels were first introduced in the 1950s following surgical complications associated with harvesting vessels, the frequent shortage of allogeneic grafts, and immunologic rejection of large animal-derived vessels. However, despite advances in pharmacology, materials science, and device fabrication, these synthetic vascular grafts have not significantly decreased the overall mortality and morbidity (Nugent and Edelman, 2003, Prabhakaran et al., 2017). Synthetic grafts continue to exhibit a number of shortcomings that have limited their impact. These shortcomings include low patency rates for small diameter vessels (< 6 mm in diameter), a lack of growth potential for the pediatric population necessitating repeated interventions, and the susceptibility to infection. In addition to grafting, vascular conduits are also needed for clinical situations such as hemodialysis, which involves large volumes of blood that must be withdrawn and circulated back into a patient several times a week for several hours.
In addition to large-scale vessel complications, ischemic diseases also arise at the microvasculature level (< 1 mm in diameter), where replacing upstream arteries would not address the reperfusion needs of downstream tissues (Hausenloy and Yellon, 2013, Krug et al., 1966). Microvascularization has proven to be a critical step during regeneration and wound healing, where the delay of wound perfusion (in diabetic patients, for example) significantly slows down the formation of the granulation tissue and can lead to severe infection and ulceration (Baltzis et al., 2014, Brem and Tomic-Canic, 2007, Randeria et al., 2015).
In order to design advanced grafts, it is important to take structural components of a blood vessel into consideration, as understanding these elements is required for rational biomaterial design and choosing an appropriate cell source. Many of the different blood vessel beds also share some common structural features. Arteries, veins, and capillaries have a tunica intima comprised of endothelial cells (EC), which regulate coagulation, confer selective permeability, and participate in immune cell trafficking (Herbert and Stainier, 2011, Potente et al., 2011). Arteries and veins are further bound by a second layer, the tunica media, which is composed of smooth muscle cells (SMC), collagen, elastin, and proteoglycans, conferring strength to the vessel and acting as effectors of vascular tone. Arterioles and venules, which are smaller caliber equivalents of arteries and veins, are comprised of only a few layers of SMCs, while capillaries, which are the smallest vessels in size, have pericytes abutting the single layer of ECs and basement membrane. Vascular tissue engineering has evolved to generate constructs that incorporate the functionality of these structural layers, withstand physiologic stresses inherent to the cardiovascular system, and promote integration in host tissue without mounting immunologic rejection (Chang and Niklason, 2017).
A suitable cell source is also critical to help impart structural stability and facilitate in vivo integration. Patient-derived autologous cells are one potential cell source that has garnered interest because of their potential to minimize graft rejection. However, isolating and expanding viable primary cells to a therapeutically relevant scale may be limited given that patients with advanced arterial disease likely have cells with reduced growth or regenerative potential. With the advancement of stem cell (SC) technology and gene editing tools such as CRISPR, autologous adult and induced pluripotent stem cells (iPSCs) are emerging as promising alternative sources of ECs and perivascular SMCs that can be incorporated into the engineered vasculature (Chan et al., 2017, Wang et al., 2017).
Importantly, a viable cell source alone is not sufficient for therapeutic efficacy. Although vascular cells can contribute paracrine factors and have regenerative capacity, merely delivering a dispersed mixture of ECs to the host tissue has shown limited success at forming vasculature or integrating with the host vasculature (Chen et al., 2010). Therefore, recent tissue engineering efforts have instead focused on recreating the architecture and the function of the vasculature in vitro before implantation, with the hypothesis that pre-vascularized grafts and tissues enhance integration with the host. In this review, we explore recent advances in fabricating blood vessels of various calibers, from individual arterial vessels to vascular beds comprised of microvessels, and how these efforts facilitate the integration of the implanted vasculature within a host. We also discuss the extent to which SC-derived ECs and SMCs have been incorporated into these engineered tissues.
Clinical Applications
The first reported successful clinical application of TEBV in patients was performed by Shin’oka et al., who implanted a biodegradable construct as a pulmonary conduit in a child with pulmonary atresia and single ventricle anatomy (Shin’oka et al., 2001). The construct was composed of a synthetic polymer mixture of L-lactide and e-caprolactone, and it was reinforced with PGA and seeded with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). The authors demonstrated patency and patient survival 7 months post-implant, and expanded their study to a series of 23 implanted TEBVs and 19 tissue patch repairs in pediatric patients (Hibino et al., 2010). They were noted to have no graft-related mortality, and four patients required interventions to relieve stenosis at a mean follow-up of 5.8 years. The first sheet-based technology to seed cultured autologous cells, developed by L’Heureux et al., was iterated by the group to induce cultured fibroblast cell sheet over a 10-week maturation period and produce tubules of endogenous ECM over a production time ranging between 6 and 9 months. They dehydrated and provided a living adventitial layer before seeding the constructs with ECs (L’Heureux et al., 2006). Their TEBV, named the Lifeline graft, was implanted in 9 of 10 enrolled patients with end-stage renal disease on hemodialysis and failing access grafts in a clinical trial. Six of the nine surviving patients had patent grafts at 6 months, while the remaining grafts failed due to thrombosis, rejection, and failure (McAllister et al., 2009). An attempt to create an “off the shelf” version of this graft in which pre-fabricated, frozen scaffolds were seeded with autologous endothelium prior to implantation led to 2 of the 3 implanted grafts failing due to stenosis, and one patient passed away due to graft infection (Benrashid et al., 2016).
Most recently, results were reported for the phase II trial of the decellularized engineered vessel Humacyte in end-stage renal disease patients surgically unsuitable for arterio-venous fistula creation (Lawson et al., 2016). This clinical scenario offers a relatively captive patient population in which graft complications are unlikely to be limb or life-threatening, and infectious and thrombotic event rates for traditional materials such as ePTFE are high (Haskal et al., 2010). The manufacturers seeded a 6mm PGA scaffold with SMCs from deceased organ and tissue donors and decellularized the scaffold following ECM production in an incubator coupled with a pulsatile pump prior to implantation. Humacyte demonstrated 63% primary patency at 6 months, 28% at 12 months, and 18% at 18 months post-implant in 60 patients. Ten grafts were abandoned. However, 12-month patency and mean procedure rate of 1.89 per patient-year to restore patency were comparable to PTFE grafts, while higher secondary patency rates were observed (89% versus 55%–65% at 1 year) (Huber et al., 2003, Lok et al., 2013). Although Humacyte revealed no immune sensitization and a lower infection rate than PTFEs (reported up to 12%) (Akoh and Patel, 2010), there remains much work to be done to improve primary patency and reduce the need for interventions.
Harnessing the regenerative functions reported in ECs derived from adult stem cells and iPSCs offers the promise of improving TEBV patency. Mcllhenny et al. generated ECs from adipose-derived stromal cells, transfected them with adenoviral vector carrying the endothelial nitric oxide synthase (eNOS) gene, and seeded the ECs onto decellularized human saphenous vein scaffolds (McIlhenny et al., 2015). They hypothesized that through inhibition of platelet aggregation and adhesion molecule expression, nitric oxide synthesis would prevent thrombotic occlusion in TEBV. Indeed, they reported patency with a non-thrombogenic surface 2 months post-implantation in rabbit aortas. While introducing additional complexities, engineering ECs and SMCs with other regenerative, anti-inflammatory, anti-thrombotic genes could perhaps bridge the functional difference between SC-derived cells and native primary cells.
- Published in Corporate News / Blog