A Pioneering Stem Cell Therapy That Prevents the Disaster of Limb Amputation

The answer to costly high risk invasive limb salvage procedures

As our population ages and the incidence of diabetes increases, we face an international rise in arterial disease that leads to major leg amputations. Hospital bills alone for such amputations are between $30,000 and $60,000 while the follow-up costs over the three years after amputation may reach another $60,000. Only about half of those who undergo amputation successfully rehabilitate which leads to a significant incidence of mental depression and a tremendous reduction in physical activities and quality of life. For the patient, consider the post-operative pain, the need for endless visits to the clinic for wound care, rehabilitation, infection control, daily medications, prosthetics fittings, loss of work or hobbies and separation from grand kids and loved ones.  

Unfortunately, death rates following amputation reach up to 40 percent at one year and 80 percent at five years.  With 330,000 new cases of this terrible disease per year in the US alone, it’s clear that we are in need of a new approach to preventing these devastating amputations.

The condition is caused by severely impaired blood flow due to blockages in limb circulation. Dr. Darwin Eton, Professor of Surgery and a Distinguished Fellow of the Society of Vascular Surgery, has developed a breakthrough therapy to successfully treat these circulatory blockages by helping Nature do what it has done since our conception: make new vessels. No physician was involved in the engineering and assembly of the miles of vessels in our body, or in the growth of these pressurized vessels as we grew. When injured tissue heals, new vessels naturally sprout. Harnessing Nature’s innate capability is the foundation to Dr. Eton’s approach to manage poor blood flow in these patients. The current solutions are to either bypass around the blockages, or to open them using ballons, stents, and lasers. The risks of infection, bleeding, failure to succeed, and injury to other organs is significant. The costs are staggering.  The interventions do not promote new vessel formation. These interventions fail because of scarring, blood-surface incompatibility, progression of disease, or smaller blockages above or below the intervention. The need for revisions is frequent. Dr. Eton believes that by helping Nature overcome obstacles to new vessel development, Nature will then bring our awesome innate “vessel making” machinery to bear with much improved long term results over existing surgical methods. 

Over the past 35 years, Dr. Eton has treated thousands of people with chronic limb threatening ischemia, both surgically and with existing catheter based techniques. He began research in 2000 on his present strategy. In the fall of 2008 it was refined enough to enroll a couple of patients on a “compassionate use” basis to avert amputation after all other options were exhausted. It worked! Since then his team has seen how the body’s chemistry is changed to support the creation of new vessels. The biochemical findings support the documentation of increased arterial flow seen on angiogram and ultrasound. Most importantly, patients who failed traditional revascularization got better and avoided amputation.

In order for Dr. Eton’s new approach to become embraced by the larger medical community, a greater body of research with more patients at more institutions must be completed and published. This is needed to overcome the existing momentum of the surgical, hospital based procedures that fit well within the current reimbursement system. A shift in the treatment paradigm to this home based, out-patient therapy must be supported with additional research involving more doctors and influencing organizations that write the treatment standards and ultimately the payers such as Medicare and private insurance companies. Prior to performing a large, multi-institutional trial, this transformative therapy is being independently evaluated at the Clinical Research Center of University of Illinois at Chicago. The Project was recognized by Cures Within Reach Inc as the top innovation in medicine in 2016 that is nearest to achieving clinical impact.

Current Research Plan:

Rationale - Dr. Eton’s approach overcomes 8 obstacles to new vessel development: 1) Lack of pulsatile blood flow which initiates vessel growth; 2) Poor delivery of oxygenated, nutritive blood flow; 3) Poor removal of toxic metabolic byproducts; 4) Decreased dissemination of distress proteins released by the  tissue; 5) Decreased arrival of progenitor (stem) cells responsible for vessel growth; 6) Decreased number and function of circulating progenitor (stem) cells in the blood; 7) decreased immunity and 8) absent fibrinolysis (dissolution of blood clot). The first 5 issues result from critically diminished blood flow past the multiple arterial occlusions. Issues 6 and 7 are consequences of arterial disease, age, and often, diabetes. Issue 8 reflects the understanding that clot within occluded sections of artery does not get effectively dissolved. 

The Approach and Treatment - Dr. Eton's solution involves a home-based low risk well-tolerated effective treatment. Dr. Eton addresses issues 1 through 5 above by using an externally applied programmed pump (the ArtAssist® device, ACI Medical, LLC). It is worn on the calf and foot for a minimum of 3 hours daily, one hour at a time, in the seated position. Dr. Eton addresses issues 6 through 8 pharmacologically with Filgrastim (10 mcg/kg, Amgen Inc) injected just under the skin every third day for a month. Filgrastim is FDA approved for stem cell mobilization. It is used routinely for immunological support after chemotherapy treatments for cancer. Dr Eton’s team has an FDA waiver to use this medicine in the clinical trial. Dr Eton discovered that the combination of the drug and the device induces low grade fibrinolysis. This discovery followed Dr Eton’s observation of follow-up imaging scans on patients treated with this approach that previously occluded arterial segments had re-opened. 

The Process and Tracking the Progress - The trial has all required approvals, and is registered with the National Institutes of Health. Patients with severe limb-threatening disease are enrolled at the University of Illinois Chicago. George Havelka MD is the site investigator. The Clinical Research Center personnel instruct the patient on how to use the device at home and how to administer the drug. The patient’s blood will be sampled before and after using the device on the first day, and repeat the evaluation at the end of two weeks and lastly at the end of one month. After that point, the drug is no longer given, but the patient will continue to use the device as their symptoms continue to improve. They will stop using the device once they’re satisfied and have maximum improvement. The cost for this process is far lower than other approaches that use bypasses, stents, balloons, catheters, and hospitalization. Dr. Eton and his team are the first to use molecular and cellular markers associated with vascular growth and fibrinolysis to guide limb salvage. 

Lastly, beyond limb salvage, this approach has yielded supportive data for a new approach to treat other vascular disorders, including lymphedema and venous hypertension. Both affect millions of patients around the globe. The influence on a protein that inhibits tumor growth (VEGF 165b) was also identified. This is an excellent example of how research in one area of medicine can spin off to others. We need to advance this research as fast as possible. Please donate to this effort that will positively influence the care of patients worldwide.

To view a bibliography supporting each element of Dr. Eton's research, click here. Learn more about his work here and here.  

Bio

Dr. Darwin Eton has a unique background in engineering and biomechanics. While at Massachusetts Institute of Technology (MIT), he was educated in multiple basic science disciplines—including fluid mechanics, cell biology, molecular biology, and vascular biology—that formed the foundation for his career as a Vascular Surgeon. His experiences in these different fields helped him understand the evolving bodies of knowledge in each discipline; each is a piece of the puzzle related to vessel growth. The perspective he gained led to some obvious conclusions. Nature makes vessels that last and does it better than people can do with all their technologies and skill. Impediments to this natural process can arise, and correcting the biological environment in patients with impaired blood flow should help restore "nature's" capability of making vessels where needed. Dr. Eton identified the impediments to "neovascularization" and then developed a safe outpatient way to overcome these obstacles. 

This biological solution has the potential to replace the bypass surgeries and catheter-based interventions needed today to prevent amputation. As it is, the long term outcome data from these routine "artificial" interventions are less than optimal, and associated with poor durability, higher risk, and high costs. His natural cell based solution is low risk, has long term durability, and costs relatively little. He has the biochemical and angiographic data supporting remarkable clinical outcomes in people who would otherwise have had limb amputation. Over the 35 years, Dr. Eton has operated on thousands of people with chronic limb threatening ischemia at risk for amputation.

Publications

Defective CXCR4 Expression in Aged Bone Marrow Cells Impairs Vascular Regeneration.

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Enhanced Cell Therapy Strategy to Treat Chronic Limb Threatening Ischemia.

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Extracellular calcium increases CXCR4 Expression on Bone Marrow-derived Cells and Enhances Pro-Angiogenesis Therapy.

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Statin and Stromal Cell Derived Factor-1 Additively Promote Angiogenesis by Enhancement of Progenitor Cell Incorporation Into...

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Stromal Cell-Derived Factor-1 Enhances Pro-Angiogenic Effect of Granulocyte Colony Stimulating Factor.

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Effect of tissue plasminogen activator on vascular smooth muscle cells.

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Endograft Technology: A Delivery Vehicle For Intravascular Gene Therapy.

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Awards

Treatment of Limb ischemia with a Novel Cell Therapy: Cures within Reach Inc. Top Project Award, 2016

Cure Accelerator, Chicago IL March 22, 2016

Society of Vascular Surgery Distinguished Fellow, 2012

Fellow, American College of Surgeons

Journal of Vascular Surgery Distinguished and Key Reviewer Designation, 2012-2016

Castle Connolly America’s Top Doctors, 2015 and 2016

Chicago Magazine Top Doctors, 2014 and 2016

University of Southern California Physician of the Year Award

University of Illinois at Outstanding Chicago Service Award

Weiss Hospital Outstanding Service Award, 2014

Patents

Axially orienting magnetically tipped guidewires.

U.S. Patent No. 5,624,430: "Axially orienting magnetically tipped guidewires." Inventors: Eton D. Issued April 29, 1997.