Matthew Engel

Minimally Invasive Delivery of Mesenchymal Stems to the Nucleus Pulposus Using an In Situ Thermoresponsive Hydrogel

In July 2009, I passed a major milestone in my graduate research in the Department of Biomedical Engineering at Stony Brook University – I passed my qualifying exam! This literally required hundreds and hundreds of hours of work, during which I read over 50 scientific publications and synthesized them to come up with an original grant proposal. In this case, my challenge was to use a tissue engineering approach to treat degenerative disc disorder. Below, I will place my statement of interest plus a copy of the grant proposal and presentation I made. I most definitely learned a tremendous amount from this process, most of which I will be keeping private and storing away for later use. But it really teaches you how to make an effective presentation and to prepare thoroughly for a talk.

In a nutshell, the project focuses on stem cell implantation technology to treat spinal chord injuries associated with aging, and could also be applied to acute injuries.

Click on individual slides to see the full image

PROJECT SUMMARY: This proposal aims to design an in situ curable hydrogel composed of PNIPAAm-PEG capable of delivering therapeutic cells and drugs to the degenerated nucleus pulposus (NP) of an intervertebral disc (IVD). The therapeutic cells will be human mesenchymal stem cells (hMSCs) differentiated into NP-like cells by exposure to hypoxic low oxygen conditions in the presence of transforming growth factor β1 (TGF- β1). The hydrogel is composed of a solution containing 10% PNIPAAm-PEG(8000) at a 1:1600 ratio of PNIPAAm:PEG which undergoes a sol-gel transition at physiological temperatures (32°C). Modifications to the PEG molecular weight or concentration can be used to alter the hydrogel stiffness or sol-gel transition temperature. These properties will allow users to prepare cell and drug loaded solutions at ambient temperatures and then inject them into the degenerated disc, at which point they solidify in situ. The hydrogel is capable of being blended with small molecule inhibitors of nitric oxide synthase (NOS). The inhibition of NOS has been shown to increase proteoglycan content which can restore disc height to the degenerated IVD.

Download copy of grant proposal here (.pdf)

President Obama repeals ban on federal funding of embryonic stem cells – March 9, 2009

On March 9, 2009 President Barack Obama removed the ban prohibiting the use of federal tax dollars for embryonic stem cell research. Specifically, on Monday a memorandum was signed allowing the White House Office of Science and Technology Policy to begin designing a strategy for carrying out this research. The earlier ban, enacted by former President Bush prevented all federal government funding for the use and development of embryonic stem cells. During this time individual states were vying to raise capital for this work on their own via private/state joint institutes. California was the leader in this, creating a $3 billion bond to support the state universities. Unfortunately, these funds were generally witheld following the ensuing political turmoil. Developments at the local level actually point towards the probability that individual states would eventually have begun financing this research, whether or not the federal government supported it.

Bush’s federal ban on embryonic stem cell funding resulted in the use of private monies for these experiments, and drastically cut down the number of academic labs studying the system. At least 6-7 years of more rapid progress was probably lost during this time. However, it did stimulate a large body of research on the use of adult derived stem cells and new technologies for generating ES cells without destroying the embryo. Without this ban, researchers at Advanced Cell Technology may never have speant so much time attempting to isolate ES cells from living embryos using biopsies, which is does not harm the embryo and is commonly performed during preimplantation genetic diagnosis (PGD). In a nutshell, PGD allows one to geneticly test embryos for disease markers before they are implanted. This is especially useful during in vitro fertilization, in which many embryos are fertilized, screened, and then transplanted into the uterus. Those embryos which carry the disease marker are not implanted.

Many new findings were made during this time period from 2001-2009, including the discovery of stem cells in the brain and other tissues. Also, the ‘reprogramming’ of adult and menenchymal stem cells into nerves or other specialized cells will have definite long term implications for disease therapy. Will it be possible to use adult derived stem cells for regenerative medicine and treating patients? Probaby not. Was it necessary to increase the research support of ES cells if we ever hope to treat Parkinson’s disease, Alzheimer’s disease or diabetes with this technology? Definitely. With the removal of this ban, universities may once again begin receiving grants and carrying out work on these totipotent cells. Importantly, it opens the door for more clinical trials and human testing in the United States. The New York Times, the Los Angeles Times, have all been reporting on this issue. Yet very few articles have actually addressed the true ethical or scientific implications of the memorandum.

Truthfully, this decision opens up a massive can of worms regarding the ethical use of embryos and ES cells during our time. Part of the root cause of this is the fault of previous administrations which neglected to address the technological advancements and fully dissect their moral implications. Instead, what amounted to an academic moratorium on ES cell research was put into effect, while other issues such as national security, defense, and wartime tactics took precedence. Some of the critical moral and scientific questions that need to be addressed are: (1) Can ES cells be generated without destroying embryos, and of so, is this as benefical in the clinic and is it efficient? (2) Is the destruction of an embryo universally considered to be an ethical objection? For instance, one may create a cloned embryo of an existing human patient using donated eggs and a cell from that patient. The embryo can be grown in vitro and potentially used to treat his/her disease. If the embryo is killed during this process, is this objectionable? The embryo came into life purely for the purpose of saving that of another. That is more useful, and productive than what is currently allowed under existing abortion law. Abortion is considered legal (but perhaps unethical) in many cases. In some cases it is ethical, for example to save the mother’s life. Therefore, is the destruction of an embryo for saving one’s life always ethical?

Brave New World by Aldous Huxley published 1932

In reality, I do not believe we are so far away from the ‘Brave New World’ scenario. Current technologies allow one to clone thyself and simply implant said embryo into the womb. Gestation of these embryos can give rise to cloned human beings, which is currently an unethical endeavor. This is due to the unknown side effects of cloning on human beings. It is expected that cloned humans, as with other mammals such as cows, pigs, and sheep would develop age related diseases more rapidly and die prematurely. In the future, it may be possible to overcome these obstacles by using DNA from the umbilical cord, but what would be the point? In my eyes, it is imperative to set ground rules and regulations preventing these types of experiments from ever happening during our era, which may or may not have much to do with embryonic stem cell therapy. However, it must be considered as the difference between therapeutic cloning and reproductive cloning is simply the implantation of an embryo.

Ph.D. Qualifying Exam

This week, I am writing the final portion of my PhD Qualifying Exam for the Department of Biomedical Engineering at Stony Brook University. The topic requests that I develop a source of stem cells which can be delivered into the brain of Parkinson’s disease patients using an engineered biomaterial. Right now, I am doing fairly well on page 25 with about 10 pp left to write. There is a lot still to do. In summary, the project involves creating a new lines of embryonic stem cells from cloned blastocysts generated by somatic cell nuclear transfer (SCNT). Briefly, SCNT involves removing the genetic material from an unfertilized egg and inserting a donor cell and applying electric voltage inducing parthogenesis – the spontaneous fertilization of embryos. From here, one can dissect the parthogenetic SCNT embryo and extract embryonic stem cells. These can be differentiated into dopaminergic neurons and implanted into the brain. That is the part I’m working on now!