VascuStim

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VascuStim is in the business of developing treatments utilizing the innovative advancements in bioelectric stimulation controlled protein expression, stem cell homing, proliferation and differentiation combined with stem cel based mixed compositions such as amniotic fluid which has over 240 known growth factors critical and important to healthy tissue and organ development and repair.  We committed to gathering data in well controlled studies with patient safety always established first and foremost.  Our stem cell based compositions are procured and handled by an FDA HCT/P certified lab.  The company prides itself on its state-of-the-art technology and its ability to provide products of the highest standards in the industry. Our amniotic fluid and membranes are processed from donated human tissue from full term deliveries and are regulated as a human cell, tissue, or cellular or tissue-based product (HCT/P) under 21 CFR Part 1271 and Section 361 of the Public Health Service Act.
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VascuStim is a unit of Leonhardt Ventures, led by Howard J. Leonhardt, which began organ regeneration research in the 1980’s.   We completed with Dr. Race Kao and Dr. George Magovern our first stem cell repair of heart in a large animal in 1988 which was published in The Physiologist in 1989 Kao RL, Rizzo C, Magovern GJ: Satellite cells for myocardial regeneration. Physiologist 1989; 32: 220. In the 1990’s we gained world leadership positions in the development of cardiovascular balloon catheters, intravascular lungs, electro magnetic radiation and stem cell delivery catheters, aortic stent grafts and percutaneous heart valves.  Our patented stent graft still holds the world’s leading share of endovascular aortic aneurysm repairs.  In 1999 we published our first paper on bioelectric stimulation controlled limb ischemia treatment in the American Heart Association Journal CIRCULATION Circulation. 1999 May 25;99(20):2682-7. working with Dr. Shinichi Kanno.  Our team went on that year to file the first in our series of over 100 U.S. patent claims for bioelectric stimulation controlled protein expressions – https://www.google.com/patents/US20050171578.  In 2001 we made history by completing the first-in-man non-surgical stem cell repair of a human heart in The Netherlands working with Dr. Patrick Serruys, Dr. Pieter Smits, Dr. Doris Taylor and Dr. Warren Sherman – http://www.onlinejacc.org/content/accj/42/12/2063.full.pdf.   In the 2000’s our team was the first to receive FDA permission to enter first stem cell therapy clinical trials for heart repair and later combination heart and gene therapy.   Over 400,000 patients have been treated to date with Leonhardt inventions.  Our vascular related inventions have been used by more than 2000 centers worldwide in over 40 countries.  Recently we helped lead with collaborating associates limb salvage trials in Mexico and Czech Republic in 7 and 16 patients respectively with bioelectric stimulation and adipose derived cell compositions.  We worked with a team in Denmark that completed a 47 patient clinical trial in Germany and Switzerland for wireless microcurrent treatment of non-healing ulcers.  This data was published in the International Wound Journal in 2013 – http://onlinelibrary.wiley.com/doi/10.1111/iwj.12204/full.  The Leonhardt team has helped lead clinical trials for stem cell therapies at over 38 leading research centers worldwide which includes 33 leading U.S. centers – https://www.clinicaltrials.gov/ct2/show/study/NCT00526253?term=MARVEL+bioheart&rank=1&show_locs=Y#locn.  Our Chief Medical Officer, Dr. Leslie Miller, former Chief of Cardiovascular Medicine at the University of Minnesota, has been involved in over a dozen stem cell therapy cardiovascular related clinical trials.  He is co-editor of the textbook Stem Cell and Gene Therapies for Cardiovascular Disease https://www.elsevier.com/books/stem-cell-and-gene-therapy-for-cardiovascular-disease/perin/978-0-12-801888-0.  Our Scientific Advisory Board is comprised of over 30 leading clinicians and scientists with unprecedented experience in the field – http://calxstars.com/scientific-advisory-board/.
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• Amniotic membrane has abundant stem cells that one can harvest without moral and ethical concerns.

• Amniotic membrane lacks immunogenicity via a low expression or lack of expression of histocompatibility antigens.

• Amniotic membrane has the ability to produce healing with little to no scarring. Along with the indirect contribution of amniotic membrane’s anti-inflammatory effects, there has been evidence of direct reduction of scarring. Tseng and colleagues demonstrated in a laboratory study that there was a direct anti-scarring action on ocular surface fibroblasts by suppressing transforming growth factor beta (TGF-b).3 The TGF-b is responsible for activation of fibroblasts and by down-regulating this process, there is a reduction and prevention of adhesion and fibrosis.

• Amniotic membrane has the ability to impart anti-inflammatory effects by mediating pro-inflammatory cytokines such as interleukin (IL-6) and TNF-alpha. Tseng and colleagues noted that enzyme-linked immunosorbent assay (ELISA) extracts have high levels of IL-10, which counteracts inflammatory effects.3 In addition, they have found amniotic membrane down-regulates the expression and production of IL-1, and up-regulates interleukin-1 receptor antagonist (IL-1RA).

Given all these properties of amniotic membrane, this team seeks to initiate well designed studies to prove out the potential safety and efficacy of this product to heal these challenging diabetic wounds as well as treating critical limb ischemia, limb salvage and diabetic neuropathy.

Jo-Anna Reems, Ph.D. is Research Professor in the Division of Hematology and Hematologic Malignancies, Department of Internal Medicine at the University of Utah School of Medicine. She is also the Scientific Director of the University of Utah Health Care Cell Therapy & Regenerative Medicine Facility, which is FACT accredited. Dr. Reems is certified by the American Society of Clinical Pathologists as a Medical Technologist, and a Specialist in Blood Banking.

The Reems Laboratory focuses on delivering novel cellular products that have the potential to improve the quality of life for patients. In her role as the Scientific Director for the Stem Cell Facility, Dr. Reems’ vision is to create a premier Cell Therapy and Regenerative Medicine Center of Excellence for the state of Utah that facilitates the translation of cutting-edge cell therapy and tissue engineered research into clinical products that extend and improve the quality of life of individuals suffering from debilitating diseases and injuries.

Dr. Reems obtained her B.S. in Medical Technology at the University of Colorado at Boulder. She then earned her Ph.D. in Biochemistry at the University of Colorado Health Sciences Center in Denver, Colorado. After her doctoral studies, Dr. Reems completed a Research Fellowship at Fred Hutchinson Cancer Research Center, with a focus on Regulators of Hematopoiesis. Prior to joining the University of Utah as faculty, Dr. Reems functioned as the Scientific Director of the Cell Therapy Facility at Puget Sound Blood Center in Seattle, Washington.

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Amniotic fluid (AF) possesses anti-inflammatory, anti-microbial and regenerative properties that make it attractive for use in clinical applications. The goals of this study were to assess the feasibility of collecting AF from full-term pregnancies and to evaluate non-cellular and cellular properties of AF for clinical applications. Donor informed consent and medical histories were obtained from pregnant women scheduled for C-sections and infectious disease testing was performed the day of collection. AFs were evaluated for total volume, fluid chemistries, total protein, and hyaluronic acid (HA) levels. AF was also assessed with quantitative antibody arrays, cellular content and for an ability to support angiogenesis. Thirty-six pregnant women consented and passed donor screening to give birth tissue. AF was successfully collected from 17 individuals. Median AF volumes were 70 mL (range 10–815 mL; n = 17). Fluid chemistries were similar, but some differences were noted in HA levels and cytokine profiles. Cytokine arrays revealed that an average of 304 ± 20 of 400 proteins tested were present in AF with a majority of cytokines associated with host defense. AF supported angiogenesis. Epithelioid cells were the major cell type in AF with only a minor population of lymphoid cells. Cultures revealed a highly proliferative population of adherent cells capable of producing therapeutic doses of mesenchymal stromal cells (MSCs). These findings showed that significant volumes of AF were routinely collected from full-term births. AF contained a number of bioactive proteins and only a rare population of MSCs. Variations noted in components present in different AFs, warrant further investigations to determine their relevance for specific clinical applications.

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[av_toggle title=’Effect of Amniotic Fluid Stem Cells and Amniotic Fluid Cells on the Wound Healing Process in a White Rat Model’ tags=”]
Effect of Amniotic Fluid Stem Cells and Amniotic Fluid Cells on the Wound Healing Process in a White Rat Model – Click here
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[av_toggle title=’Bioelectric Stimulation + Amniotic Fluid in Diabetic Foot and Leg Ulceration’ tags=”]

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[av_toggle title=’Asadi Angiogenic effects of low-intensity cathodal direct current’ tags=”]
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[av_toggle title=’Diabetic Foot Ulcers and Their Recurrence’ tags=”]
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June 28, 2017

VASCSTIM CLINICAL PROTOCOL

Background:

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Recent data has shown that it has become the leading cause of hospital readmission and results in XXX,000 amputations each year. The most common cause of PAD is diabetes, which can cause conduit vessel disease, but more commonly results in occlusion of the microvasculature. This microvascular form of PAD, is not very responsive to current surgical or catheter based revascularization therapy. It typically results in non-healing ulcers once a skin breakdown occurs, despite the use of several current treatment options including hyperbaric oxygen and various dressings. Non-healing ulcers results in significant morbidity, but also significant health care costs which have been recently estimated at over $xx million/year.

These data provide the stimulus for identification of new treatment options. Two of the most promising are use of low current Bioelectric Stimulation (BES) and amniotic fluid and membranes(AF) in patients with or without the diagnosis of diabetes.

GOAL:
The goal of this registry is to document the ability of the combination of BES and AF in improve the size and depth of non-healing ulcers due to PAD.

Description: This is a prospective, non-randomized, non-blinded, interventional, consecutive series Registry study to determine initial safety and efficacy of a series of treatments with bioelectric stimulation controlled protein expression followed by use of AF as a membrane laid onto the ulcer, with or without additional use of injected AF around the ulcer in the treatment of non-healing skin ulcers of leg or foot due to PAD.

The study, including the protocol and consent form will have been approved without stipulations by a local or certified Institutional Review Board as meeting safe and good clinical practice before any subject will be enrolled.

Inclusion Criteria:

1. Age 18-80 yrs of age
2. Non-healing skin ulcer of leg or foot > 2 cm in diameter

• Able to tolerate up to 40 minutes of BES on the non-involved leg or foot

4. Able and willing to make the required study visits.
5. Able and willing to give informed consent and follow study instructions.
6. Must speak, read, and understand English

• Agree to allow photographs to be taken of the ulcer before and at the end of the treatment period to document change.

Exclusion Criteria:

1. Use of concomitant treatments to improve wound healing, including topical medications, oral medications, hyperbaric oxygen therapy, non-ablative fractional laser treatment, low-level laser therapy, PRP injection within the preceding 2 months.
2. Allergic to lidocaine or epinepherine
3. Planned revascularization procedure in next 3 months
4. Individuals with diminished decision-making capacity
5. Renal replacement therapy
6. Pregnancy or lactating period for females

Target Number of Participants:  300

Target Number of Enrolling Sites: 30

Screening:

Any subject with a non-healing ulcer of >2 cm in diameter who meet all Inclusion and Exclusion criteria will be eligible for participation. Each potential subject will have a brief history and examination performed by the Investigator, and if acceptable, will be provided with an overview of the Registry and then provided with the Consent Form.  If they choose to participate, and sign the Consent form, they will be enrolled in the Registry.

Baseline Evaluation:

All potential enrollees will have been evaluated by a certified vascular surgeon or physician who stipulates that the patient has a significant ulcer of the foot or leg is not responsive to all common treatments.

Before the procedure, a baseline photo will be taken of the planned treatment ulcer to compare to the measurements at the end of treatment period of 12 weeks.

Intervention:

Screening Treatment Bioelectic Stimulator:

All participants will have two standard electrical conductive skin patches or electro acupuncture needles applied in the region near the ulcer and connected to a bioelectric stimulation signal generator that has been previously tested and proven to be capable of delivering the required current.

The stimulator is capable of transmitting specific signals will be applied first to the uninvolved leg or foot. It will run through up to a 40 minute cycle of protein release signals to stimulate the release/increased expression of a number of growth factors that have been extensively shown to stimulate both the growth of new blood vessels and recruitment of stem cells to enhance native wound healing, initially including: SDF-1, and transitioning through IGF-1, HGF, EGF, eNOS, VEGF, Follistatin, Tropoelastin, and Activin A+B. If well tolerated, the patient will be eligible to participate in the Registry and treatment of the involved leg or foot.

Treatment with Amniotic Membrane with or without  Amniotic Fluid (AF) Injection:

Each patient enrolled in the Registy will receive a single covering of the ulcer with an appropriate sized Amniotic Fluid Membrane, which will be provided by Bioleonhardt VASCSTIM, and reconstituted with several cc’s of Amniotic Fluid and laid directly onto the ulcer/wound.
The decision to also inject up to 5 cc’s of Amniotic Fluid will be made by the patient’s vascular surgeon or physician in advance of the treatment  and injected at equal spacing into 8-10 sites approximately 2-3 centimeters from the edge of the wound in a circumferential pattern, with or without the use of lidocaine anesthesia at the patient’s choice.

A non-adhesive dressing will be applied over the Amniotic Membrane and wound at the completion of this treatment and a fresh dressing maintained over the wound for a minimum of 10 days, and then may remain uncovered at the discretion of the treating physician/

Treatment Schedule:

The treatments will take place for a period of 40 minutes, 3 times/week  for 12 weeks to demonstrate the safety and benefit of the planned therapy.

Follow Up Evaluations:

At the end of 6 and 12 weeks, a photo will be taken of the wound being treated to measure and document the response to treatment.

The goal is complete healing of the wound by the end of the treatment.

Each subject will also have a brief interview inquiring about any adverse effects noted by the subject since enrolling in the Rtudy, and an examination by the Principal Investigator for any adverse effects of the therapy including damage or injury.

End Points:

Co-Primary Outcome Measure:

1. Incidence of treatment-related adverse events by the end of the treatment period, to include, but not exclusively: local itching, bleeding, pain, swelling, local pain, or headache, visual changes, palpitations, or nausea, AND
2. Percentage of wound healed by the end of the treatment period as assessed by quantitative measurement of the size of the wound.

Secondary Outcome Measures:

1. Any adverse events not described above
2. Incidence of need to terminate the study for pain or other cause
3. Failure of the Bioelectric Stimulator

1. Stopping Rules:

The Registry will be paused if a total of 3 of the study subjects experience a treatment-related side effect of at least moderate severity. It will be restarted when additional investigation yields a clear cause and effective action plan has been implemented.

Data Analysis:

Data will be collected for each patient and analyzed at three time points including the end of the first 100 patients, the end of 200 patients, and when the last enrolled individual has reached the 6 month post treatment time point. The Registry may be stopped if the data demonstrates a > 67 % complete wound healing at the end of the 12 week treatment period.

Additional subjects may be enrolled into the study if approved by the IRB and Sponsor.
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