Future of Regenerative Medicine with Kyle Cetrulo of AuxoCell

I had the honor of interviewing Kyle Cetrulo, CEO of AuxoCell Laboratories. In this interview, we explore the upcoming Future of Regenerative Medicine Congress, as well as future directions for regenerative medicine at large. Enjoy. 

Interview with Kyle Cetrulo, CEO of AuxoCell Laboratories

Cade Hildreth: What is your background and how did you become involved with regenerative medicine?

Kyle Cetrulo: Thank you for inviting me to this interview and to share information about the upcoming 3^rd Annual Perinatal Stem Cell Congress.  Our meeting is called The Future of Regenerative Medicine Congress:  Extending and Improving Life with Perinatal, Adipose and Bone Marrow Stem Cells and takes place May 19-21 at the Teaneck Marriott in Teaneck, NJ.  www.presentregmed.com is the conference website for information and to register for the conference. 

Use the CODE “BIOI” for a $100 discount off of the $499 conference registration fee.

I began my career in the cord blood field in 1998 when I became the Director of the non-profit International Cord Blood Society (ICBS).  The International Cord Blood Society was an organization that was co-founded in 1991 by my father, Dr. Curtis L. Cetrulo, and Dr. Anthony Sbarra to bring the handful of researchers working in the cord blood field at that time together to advance the field.  When the first meeting of the ICBS took place (Meeting years: 1992, 1995, 1996,1997, 1998, 2004), there were no cord blood banks and the concept of cord blood use for transplantation was truly revolutionary.

Reviewing the programs from these early cord blood events, it is not surprising that the faculty was composed of all of today’s thought leaders.  The lecture topics also make an excellent timeline for the history of the cord blood field.¹ For those interested, I include a few of the classic papers from this time period in the references and also provide 2 excellent review articles on the history of cord blood transplantation.^2-9

Cade Hildreth: What are perinatal stem cells, and how did you get involved with the Perinatal Stem Cell Society?

Kyle Cetrulo: Perinatal stem cells are stem cells that are derived from afterbirth (perinatal) tissues such as the amnion, chorion, placenta (including both placental blood cells and tissue), umbilical cord blood (UCB) and umbilical cord tissue (Wharton’s Jelly).  Perinatal stem cells are classified as adult stem cells but they really are more primitive than stem cells found in adult sources, such as bone marrow, adipose tissue or other traditional sources of adult stem cells. Since perinatal stem cells are more primitive than adult stem cells, they have greater therapeutic potential.

In 2004, when we hosted the 6^th International Cord Blood Society Congress, cord blood banking was well established and cord blood transplantation was considered a standard of care treatment option.  By 2004, over 10,000 UCB transplants had occurred worldwide.  During the early 2000s, mesenchymal stem cells (MSCs) were beginning to make a splash in the medical literature and I became interested in the regenerative potential of MSCs.¹⁰ In 2003, Drs. Kathy Mitchell and Mark Weiss published a paper that identified the Wharton’s Jelly of the Umbilical Cord as a rich source of MSCs and we invited them to speak at the 2004 meeting.¹¹

I was also well aware of the Placenta, as well as the Amnion and Chorion, as rich sources of stem cells. At this time, my father and I were invited to guest edit an issue of the journal “Stem Cells Reviews” with a focus on perinatal stem cells.  As we worked to compile this journal, we did an extensive review of the published literature at the time to find the world’s leading experts for the journal issue and we both became firmly convinced that the most efficacious cellular therapies would be derived from perinatal stem cells.  My father came up with the title “Everyone Is, or Should Be, Interested in the Placenta,” for the introduction to the Stem Cells Review Journal, and he correctly made the following two predictions in our introduction.

“Perhaps we should begin to think about saving all placentas and banking the cells collected from other tissues in the placenta including HUVECS, UCM cells*, AE cells, mesenchymal cells collected from various tissues of the placenta, and HSCs from the umbilical cord blood. All of these cells or various combinations of these cells may be used in the future to saves lives and enhance the quality of life for many people.  We might envision a time when a child is born and the placenta is saved and a “cocktail” of these elements might be used to treat hypoxic ischemic encephalopathy (HIE) in the newborn during the peripartum period for neurogeneration.”¹² Today, some of the most exciting work taking place in the cord blood field are the clinical trials to treat neonatal brain injuries such as Celebral Palsy and HIE with cord blood and cord tissue derived stem cells.

(*Note: UCM cells stands for Umbilical Cord Matrix cells, which today would mean Cord Tissue/Wharton’s Jelly derived cells.  “Cord tissue” was not a term of art yet for the source of these cells as this was a term that the private cord blood banks coined to make the source of stem cells easier to understand for their customers.)

Following the completion of the “Stem Cell Reviews” Journal Issue, I became convinced that the banking of the umbilical cord tissue/wharton’s jelly would be a product offering in the umbilical cord blood industry.  In 2008, along with Dr. Rouzbeh Taghizadeh, we formed Auxocell Laboratories, Inc. (Auxocell) to develop new and better ways of processing cells from perinatal tissues.  This remains the primary focus for Auxocell 9 years later.

Today, we offer a single use, disposable processing system called the AC:Px.  Without the use of an enzymatic digestion step, the AC:Px fractionates solid tissues such as the entire umbilical cord, amnion,  adipose and even solid organs into 3 products.  The first product is a single cell suspended product consisting of the native cells comprising the tissue, the second product is a minced tissue product and the third product is a de-cellularized extracellular matrix (secretome) product (www.auxocell.com)

Cade Hildreth: Can you tell us more about the Perinatal Stem Cell Society?

Kyle Cetrulo: After editing of two books titled “Perinatal Stem Cells” (2009) and “Perinatal Stem Cells, Second Edition” (2012), Dr. Taghizadeh and myself decided to partner with Dr. Sean Murphy from the Wake Forest Institute of Regenerative Medicine (WFIRM) to form a new non-profit society called the International Perinatal Stem Cell Society Inc. and in 2013, the society was incorporated as a non-profit 501(c)(3) organization.^13,14 A new Perinatal Stem Cell Book is in process, titled “Perinatal Stem Cells: Research and Therapy”, which we are co-editing with Dr. Anthony Atala and Dr. Murphy from WFIRM.

The goal of the Perinatal Stem Cell Society is to advance perinatal derived therapies to the clinic and bring the safest and most efficacious cellular therapy treatment options to patients.  Although the Society has had many successes, I was particularly proud of the fact that the Perinatal Stem Cell Society was able to gather over 35,000 signatures in support of the REGROW ACT that ultimately passed as part of the 21^st Century Cures Act.  These signatures were presented to members of congress along with over 700 pages of comments urging action and a Yes vote on the Cures Act.  I like to think that our work had some influence on the passing of this Act and ultimately on the use of perinatal stem cells for the benefit of future patients.

In 2014, we held our first international congress in Berkeley, CA and our second international congress was held in 2016 in Aspen, CO.  Our third international congress is scheduled to take place May 19-21, 2017 in Teaneck, NJ.  For this congress, we have partnered with PRESENT e-Learning Systems and we have expanded the educational platform to be reach a broader regenerative medicine audience.  The Future of Regenerative Medicine Congress is a 3-day event and includes additional talks that focus on Adipose, Bone Marrow and PRP cell sources, as well as on Biomaterials and 3D printing lectures.

The reason for this expanded educational platform is because Adipose and Bone Marrow derived treatment options represent the front line of stem cell therapy treatment options currently taking place in the United States.  I believe that the perinatal stem cell focused field can learn a great deal from hearing about the experiences that Adipose and Bone Marrow focused clinicians and clinics are undergoing.  As we are all part of the regenerative medicine industry, we share many of the same challenges whether regulatory, manufacturing, reimbursement or otherwise.

I believe that our best path forward is to work together as an industry to overcome all of the obstacles facing the entire regenerative medicine field.

Cade Hildreth: How would you describe the Future of Regenerative Medicine Congress being held over May 17-19th, 2017?

Kyle Cetrulo: The Future of Regenerative Medicine Congress:  Extending and Improving Life with Perinatal, Adipose and Bone Marrow Stem Cells, takes place May 19-21 at the Teaneck Marriott in Teaneck, NJ.  www.presentregmed.com is the conference website for more information and to register for the conference.  Use the CODE “BIOI” for a $100 discount off of the $499 conference registration fee.

The goal of the conference is to bring attendees up-to-date with evidence-based research and products derived from Perinatal Tissues such as Amnion, Amniotic Fluid, Cord Blood, Cord Tissue and Placenta, Adipose tissue as a source of mesenchymal stem cells and Bone Marrow, along with advanced wound care and other important medical interventions.

The Congress is designed for researchers and frontline medical practitioners such as Plastic Surgeons, Orthopedic Surgeons, Podiatrists, Nurses and any clinician or scientist working in the field of regenerative medicine. The Congress will bring together healthcare professionals, researchers, and any clinician or scientist working in the field of regenerative medicine who wishes to improve patient outcomes and most importantly, to collaborate on the development of new and exciting therapies.

Cade Hildreth: What speakers are you most excited to hear present?

Kyle Cetrulo: Bringing a first class faculty together is a trademark of all of the Perinatal Congresses and the Future of Regenerative Medicine Congress is no different.   Our faculty is comprised of leading clinicians and researchers from the world best research institutions.

Here are some of the talks I am most looking forward to hearing.

“Regenerative Medicine: Current Concepts and Changing Trends”
Anthony Atala, MD Anthony Atala, MD, (Conference Chair), Director, Wake Forest Institute for Regenerative Medicine, H. Boyce Professor and Chair of Urology, Wake Forest School of Medicine Professor.

Patients with diseased or injured organs may be treated with transplanted tissues. There is a severe shortage of donor organs and tissues which is worsening yearly due to the aging population. Regenerative medicine and tissue engineering apply the principles of cell transplantation, material sciences, and bioengineering to construct biological substitutes that may restore and maintain normal function in diseased and injured tissues. Stem cells may offer a potentially limitless source of cells, and 3D bioprinting applications are being utilized for potential therapies and body-on-a-chip technologies for drug discovery and personalized medicine.  Recent advances that have occurred in regenerative medicine will be reviewed. Applications of these new technologies that may offer novel therapies for patients with tissue injury and organ failure will be described.

“The Evolution of Orthobiologics”
Adam W Anz, MD, (Conference Chair)

Dr. Anz is an orthopedic surgeon and sports medicine specialist dedicated to serving patients at the world-class Andrews Institute where he has an expanded focus on autologous stem cell research and joint preservation surgery. Biologics have not only arrived in the Orthopaedic community over the past ten years; they have also evolved.  While some technologies have faltered when tested, there are clear wins on the board.  Leveraging orthobiologics in clinical practice requires an understanding of the developmental history of these technologies and what principles are used to harvest, process, and deliver them, so that as clinicians we can improve the biology of what we do.

“Game Changer: Using Cord Blood to Help the Brain.”
Joanne Kurtzberg, MD; Director, Carolinas Cord Blood Bank; Chief Scientific Officer, Robertson Clinical and Translational Cell Therapy Program; Director, Pediatric Blood and Marrow Transplant Program

Cord blood cells can work through paracrine and trophic mechanisms to help endogenous cells heal brain tissue damaged by disease or injury. Learning from observations made using unrelated donor umbilical cord blood transplantation after myeloablative chemotherapy to treat children with certain inherited metabolic diseases, cord blood therapies have been developed to treat children with acquired brain injuries, like hypoxic ischemic encephalopathy, cerebral palsy, and autism. Results of preclinical and IND enabling studies will be presented to provide information about safety and potential mechanisms of action of cord blood cells in this setting. Data from early phase human clinical trials for safety and efficacy in these diseases will be presented by the speaker in this session.

“Understanding and predicting the effect of biomaterials on cell and stem cell differentiation.”
Professor Joachim Kohn, PhD, Board of Governors Professor Director, New Jersey Center for Biomaterials Chair, International College of Fellows (ICF-BSE)

Almost all regenerative therapies that are currently being developed include cells and stem cells as the key constituents.  In many instances simple injection of cells fails to have an optimal outcome.  Instead, in many applications relating to the regeneration of lost or damaged tissue, cells and stem cells need to be delivered to the patient as part of a cell-seeded scaffold.

This lecture will review the way artificial materials interact with and influence cells.  This lecture will also show innovative ways to create bioactive scaffolds, e.g., scaffolds that can direct stem cells to differentiate along a desirable lineage. The potential of high-content imaging and computational modeling of cell-material interactions will be highlighted.  Research that increases our understanding of cell-material interactions will be discussed.

“Wharton’s jelly to augment cleft palate repair strategies.”
Charles S. Cox, Jr, MD, Professor of Pediatric Surgery, and the George and Cynthia Mitchell Distinguished Chair in Neuroscience, directing the Pediatric Surgical Translational Laboratories and Pediatric Program in Regenerative Medicine at the University of Texas Medical School at Houston.

Cleft palate is common congenital craniofacial abnormality that requires staged reconstruction with multiple operative procedures, usually including alveolar bone grafting. Often, cleft palate is diagnosed in utero via ultrasound. Wharton’s jelly is a natural hydrogel that contains MSC embedded in the matrix. We have developed a process for isolating the hydrogel/cell combination product (USPTO provisional patent 62/303,817) for use as a thixotropic gel for use in the repair of cleft palate and other indications.

We have demonstrated long term enhanced bone regeneration in animal models of a critical alveolar cleft defect using microCT, histology, and bone morphometric analyses using a Wharton’s jelly augmented gingivoperiosteoplasty approach.  These data have formed the basis for translating these data into a new surgical repair strategy for patients with cleft palate.

Please visit the conference website for a full list of confirmed faculty at www.presentregmed.com.

Cade Hildreth: How are FDA regulations affecting the regenerative medicine space?

Kyle Cetrulo: The California Institute of Regenerative Medicine (CIRM) really does a great job of outlining the case for reform of the FDA pathways in the CIRM 2016 Strategic Plan.

“A striking 70% of CIRM stakeholders identified the FDA as the number one impediment to achieving the mission. Perhaps this is because there have been no stem cell treatments approved (nor are any near approval) in the United States despite the conduct of stem cell clinical trials for more than two decades. While effective regulation and oversight of all therapies, including stem cell treatments, is clearly necessary and desirable to protect patients’ interests, stem cells present unique challenges that the current regulatory paradigm does not adequately address.”¹⁵

Hopefully, with the passing of the 21^st Century Cures Act, we will see safe cellular therapies reach patients in the United States.  I was a big proponent of the passing of the REGROW ACT and the Perinatal Stem Cell Society was quite vocal on the topic.  The 21^st Century Cures Act does include a fast track designation for cellular therapies however the version that was passed via the Cures Act requires that the cellular therapy meet an unmet medical need.  I was very disappointed to see that this change was made to the original REGROW ACT language because I believe if a cellular therapy is shown to be safe and efficacious it should not have to meet the “unmet medical need” standard but simply the unmet need of a patient who would benefit from that cellular therapy.

At the Future of Regenerative Medicine Congress, our Conference Chair, Adam W. Anz, M.D. will give a talk titled the “Regulation of Biologics from a Clinical Perspective” and this talk will be followed by a Panel discussion with leading experts that will focus on the latest FDA Guidelines and future directions that regulation may take in the United States.

Cade Hildreth: What trends do you see that will likely affect the regenerative medicine space in the next 3-5 years? Next 5-10 years?

Kyle Cetrulo: I like to begin any presentation that I give with an image of a baby floating in amniotic fluid, attached to the umbilical cord that allows the mother to provide nutrients to the fetus (see right). I start each of my talks with this image, because I like to remind the audience that the entire goal of regenerative medicine is to attempt to replicate the natural processes that have been honed to perfection via the evolution of the human species over millions of years.  The uterus is the ultimate Bioreactor as two cells come together and create a complete human being.

I think that over the next 5-10 years we will see the field move in a direction to return to these natural processes.   The most obvious way to do this in my opinion is to take advantage of the native perinatal cells and tissues.  By native cells, I am referring to the natural resident cells that comprise a given tissue. Native cells are unchanged and left in their original form and  (when within the tissue) to the greatest extent possible.

Changes to the original native cells occur during the “normal” course of product development for any number of reasons but some of the most common practices in the field include exposing tissue to chemicals or enzymes in order to break down the tissue and release the cells and culturing the cells to expand the cells in order to create a homogenous artificial cell product and/or simply to grow more cells for larger doses.

I think that there is a big misconception in the cellular field that more cells equals better outcomes in the patient and this is not necessarily true. What really effects better outcomes are more potent cells not simply more cells that have lost their potency during the manufacturing process.  We believe that the most potent cells are the natural, native cells. Once you expand these cells ex vivo, the cells are no longer the same native cells used to seed the cultures since they senesce quicker and lose their potency with each ex vivo division.

I think that the success that 361 regulated products derived from placenta, amnion and umbilical cord have had in the clinic speaks volumes to the therapeutic power of the native cells and tissues.  By definition, 361 regulated products attempt to stay as close as possible to the original source of cells and tissue from which the products are derived.   I hope that the FDA recognizes this potential and expands on the indications for use for 361 regulated products rather than limit their use.

Cade Hildreth: How can people learn more about the upcoming Future of Regenerative Medicine Event or get registered to attend

Kyle Cetrulo: I would encourage everyone interested in cellular therapy and the regenerative medicine field to attend the Future of Regenerative Medicine Congress.

The Future of Regenerative Medicine Congress:  Extending and Improving Life with Perinatal, Adipose and Bone Marrow Stem Cells, takes place May 19-21 at the Teaneck Marriott at Glenpointe in Teaneck, NJ.  www.presentregmed.com is the conference website for more information and to register for the conference.  To register for the event please visit https://regmedcongress.com/ and use the CODE “BIOI” for a $100 discount off of the $499 conference registration fee.

Thank you for this opportunity to share some of my perspectives on the Regenerative Medicine field and to introduce the Future of Regenerative Medicine Congress to your audience.

References

1. ICBS Past Meetings
2. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. 1989;321(17):1174–1178.
3. Wagner JE, Broxmeyer HE, Byrd RL, et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood. 1992;79(7):1874–1881. [PubMed]
4. Kohli-Kumar M, Shahidi NT, Broxmeyer HE, et al. Haemopoietic stem/progenitor cell transplant in Fanconi anaemia using HLA-matched sibling umbilical cord blood cells. Br J Haematol. 1993;85(2):419–422. [PubMed]
5. Wagner JE, Kernan NA, Steinbuch M, Broxmeyer HE, Gluckman E. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet. 1995;346(8969):214–219.
6. Kurtzberg J, Laughlin M, Graham ML, et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med. 1996;335(3):157–166. [PubMed]
7. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1998;339(22):1565–1577.
8. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122(4):491-498. doi:10.1182/blood-2013-02-453175.
9. Munoz J, Shah N, Rezvani K, Hosing C, Bollard CM, Oran B, Olson A, Popat U, Molldrem J, McNiece IK, Shpall EJ. Concise review: umbilical cord blood transplantation: past, present, and future. Stem Cells Transl Med. 2014 Dec;3(12):1435-43.
10. 10. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991 Sep;9(5):641-50.
11. Mitchell KE, Weiss ML, Mitchell BM, et al. Matrix cells from Wharton’s jelly form neurons and glia. Stem Cells. 2003;21:50–60. [PubMed]
12. STEM CELL REVIEWS, vol. 2, no. 2, 2006 https://www.ncbi.nlm.nih.gov/pubmed/17237544. Cetrulo CL, Cetrulo KJ. Placental and pregnancy stem cells: everyone is, or should be, interested in the placenta. Stem Cell Rev. 2006;2(2):79-80.
13. Curtis L. Cetrulo (Editor) Kyle J. Cetrulo (Editor), Curtis L. Cetrulo, Jr. (Editor). Perinatal Stem Cells. Hoboken, NJ: Wiley-Blackwell; 2009 http://onlinelibrary.wiley.com/book/10.1002/9780470480151
14. Cetrulo KJ, Curtis L. Cetrulo J, Taghizadeh RR, editors. Perinatal Stem Cells. Volume 2: John Wiley & Sons, Inc.; 2013. http://www.wiley.com/WileyCDA/WileyTitle/productCd-1118209443,subjectCd-LS60.html
15. https://www.cirm.ca.gov/sites/default/files/CIRM_StrategicPlan_2016.pdf (p.20).