CAUTION:  Investigational device. Limited by Federal (or United States) law to investigational use.
 
Bioelectric + light therapy stimulation and amniotic fluid combination designed to treat:
 
1.  Critical limb ischemia.
2.  Diabetic foot and leg ulcers.
3.  Diabetic neuropathy.
4.  Limb salvage.

                   

This informational brochure does not represent that the device is safe or effective for the purposes for which it is being investigated. 21 CFR 812.5(b).
 
VascuStim is a combination product of a bioelectric stimulator that controls release of SDF-1 (stem cell homing signal), IGF-1, EGF, HGF, PDGF, VEGF, eNOS, Activin A+B, Follistatin, Tropoelastin, IL-6 and HIF 1 Alpha on demand.  It also has signals to control stem cell proliferation and differentiation.  The second component of the combination product is minimally manipulated highly concentrated amniotic derived membrane specifically developed for peripheral vascular healing.  It’s conjointly been shown to promote tissue regeneration by providing an anti-microbial and anti inflammatory atmosphere at surgical and wound sites.  VascuStim is the first combination product to include minimally manipulated material from amniotic fluid and membranes and controlled stem cell homing, proliferation and differentiation via bioelectric stimulation with precise controlled expression of demand of over 12 proteins known to promote tissue regeneration and healing.  VascuStim published their first stem cell repair study in The Physiologist with Dr. Race Kao in 1989 and their first bioelectric limb salvage study in the American Heart Association Journal CIRCULATION with Dr. Shinichi Kanno.   We published our first stem cell clinical trial results in the Journal of the American College of Cardiology with Dr. P. Smits in 2003 (see below reference information in Unmatched Experience section).   Over 40 papers have been published worldwide, many by VascuStim and Leonhardt Ventures associated researchers, documenting the safety and efficacy of bioelectric and microcurrent wound healing and also stem cell + growth factors tissue regeneration and healing.  The combination herein described has not yet been studied as a combination product yet and safety and efficacy of this combination is unknown at this time. 
 
VascuStim a Leonhardt Ventures company incubating in the Leonhardt’s Launchpads by Cal-X Star Business Accelerator, Inc. startup innovation accelerator(s) is seeking investigators input at this time for the final product design and the design of pre-clinical and clinical studies to prove our this combination therapy for the above mentioned indications of use.

VascuStim

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.

UNMATCHED EXPERIENCE

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  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/.

UNMATCHED EXPERIENCE

Amniotic membrane is placental tissue that comes from donated placenta after childbirth. It consists of the innermost layer of tissue that is comprised of a thin epithelial layer, a thick basement membrane and an avascular stroma.
There are several unique properties of amniotic membrane that make it ideal for wound healing.
• 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.

The way the amniotic tissue is processed also makes a difference in maintaining the integrity of the amniotic membrane.  The VascuStim team sources amniotic fluid and membranes from the patent pending processes developed at the Reems Lab at University of Utah.  Dr. Joanna Reems has over 20 years experience processing and studying amniotic fluid for therapeutic purposes.
 
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.

Abstract

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.

Specifications Bioelectric Stimulator U.S. FDA 510K Market Clearance No. K113017:

Programmability •Five custom, preset user programs •Each program offers 10 treatment phases •In TENS mode channels 1 and 2 can be programmed independently Safety •Self-diagnosis •Constant current output •Zero start of output •Detection of abnormal pulse output •Keylock •UL listed and CE certified Versatility •EMS, TENS, and Microcurrent therapies •Memory backup •Low battery power warning message •Optional AC adapter (120V or 230V, 50/60 Hz)
Output channel: 2 channels, independently controlled Pulse Shape: Symmetric, biphasic rectangular pulse. (1) TENS & EMS (200 Ω – 1 kΩ load) f: pulse frequency PW: pulse width Vp: output voltage Ip: output current *Ip: vp/ 500 Ω (2) Microcurrent [f+]=[f-]=f (pulse frequency) [PW+]=[PW-]=PW (pulse width) (500O – 50 kΩ load) f= pulse frequency PW: pulse width Vp: output voltage Ip: output current *Ip: vp/ 50 kΩ 1/f Vp PW 1/f+ 1/fPW+ PW- 0 + – Vp Output current: Constant current, peak value display Max. 80 mA at 500 Ω load ···TENS, EMS Max. 750 µA at 50 kΩ load ···Microcurrent At maximum output setting Maximum charge per pulse Maximum average current TENS 20 µCoulomb 4 mA EMS 24 µCoulomb 2.4 mA MCS 187 µCoulomb 0.3 mA Pulse width: 50-250 µs ··· TNS 100-300 µs ··· Muscle Stimulation 1-250 ms ··· Microcurrent Pulse rate: 1-200 Hz ··· TNS Pulse rate and width can be set independently on each channel in Constant mode. 25-100 Hz ··· Muscle Stimulation 0.3-400 Hz ··· Microcurrent Output mode: (1) TNS: Constant, Burst, Modulation, Dual Frequency. (2) Muscle Stimulation: Hold time: 0.5-30 sec. Rest time: 1-60 sec. Ramp Up/Down time: 0. 6 sec. (3) Microcurrent Constant only (4) Program: up to 5 programs Programming capability: Number of programs···5 Steps per program·····10 Timer: 30-minute digital timer, with accuracy of +/-2% Display: LCD (46 mm x 37 mm) Other functions: Memory of the previous setting parameters and mode, keyboard lock, automatic power off, low battery power detection, abnormal pulse output detection and electronics self-test. Power source: Dual power source with DC 9 V battery or AC (AC adapter optional) Classification: Class II / internally powered equipment, TYPE BF Conformity: CE Marking UL listed: E203404 Size: 113 mm (H) X 2.7 in (W) X 25 mm (D), (4.4 in (H) X 2.7 in (W) X 1.0 in (D) Weight: 185 gr. (6.5 oz). Including a battery Environment for transport and storage: Temperature: -10°C – 60°C (14°F – 140°F) Humidity: 30% – 80% Specifications and designs are subject to change without prior notice. 215_specs_RevB_07/7/14

References:

Effect of Amniotic Fluid Stem Cells and Amniotic Fluid Cells on the Wound Healing Process in a White Rat Model

Effect of Amniotic Fluid Stem Cells and Amniotic Fluid Cells on the Wound Healing Process in a White Rat Model – Click here

Bioelectric Stimulation + Amniotic Fluid in Diabetic Foot and Leg Ulceration

Purpose

The investigators hypothesis that use of a bioelectric stimulator device, that recruits stem cells via a homing signal and increases blood flow to the leg and foot, will speed up ulcer healing in symptomatic diabetes when used in combination with amniotic fluid membrane applications on the wounds.
Condition Intervention
All Subjects Will Receive Best Medical Therapy. Those Randomised to Device Will Additionally Use the Device Device: VascuStim bioelectric stimulator deviceBiologic:  Amniotic fluid membraneOther: Best Medical Therapy
Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Bioelectric Stimulation  + Amniotic Fluid in Diabetic Foot and Leg Ulceration
Resource links provided by NLM:
Further study details as provided by VascuStim a Leonhardt Ventures Co.
Primary Outcome Measures:

  • Ulcer healing [ Time Frame: 16 weeks ]
    Time to 50% healing of leg ulcer, as measured by volume (3D camera)


Secondary Outcome Measures:

  • Quality of life [ Time Frame: 16 weeks ]
    Improvement in quality of life questionnaire values, comparing baseline to 6 weeks with treatment
Target Enrollment: 300 to 1200 patients
Expected Study Start Date: October 2017
Expected Study Completion Date: December 2018
Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: No device

Treated with best medical therapy
Other: Best Medical Therapy

Seen in outpatient clinic for wound care and ongoing advice
Experimental: Device + Biologic

As well as receiving best medical therapy, these people will be given the VascuStim device therapy via stimulation electrodes applied on their affected leg. They will be stimulated for 2 hours every three days during a 16 week course of treatment.  Amniotic fluid membranes will be placed on all wounds with renewed application every ? days.
Device: VascuStim bioelectric stimulator device

Placed on the lateral aspect of the knee, when activated it causes the leg to twitch + amniotic fluid membrane placed on wounds

Other: Best Medical Therapy

Seen in outpatient clinic for wound care and ongoing advice

Detailed Description:

Diabetes affects approximately 347 million people worldwide, and by 2030 the WHO projects that diabetes will be the 7th leading cause of death. Diabetic foot ulcers are estimated to occur in 15% of all patients with diabetes, often co-existing with neuropathy and peripheral vascular disease which compromise the limb’s ability to heal. Foot infections in this cohort are common, and diabetic foot ulcers serve as a portal for infective organisms to enter the body. Unchecked, infection can spread contiguously to involve underlying tissues, including bone. A diabetic foot infection is often the pivotal event leading to gangrene and lower extremity amputation. Diabetes accounts for over one million leg amputations every year, and represents 60% of all amputations in developed countries.
Due to the potential for rapid progression of infection, and the gravity of potential complications, diabetic foot problems are handled aggressively in the community, with a low threshold for referral to secondary care. Out-patient clinics involve a multidisciplinary team of clinicians, podiatrists and vascular surgeons. Good foot care is taught to all diabetic patients, and treatment with antibiotics, debridement and revascularisation should occur as a matter of urgency where appropriate.
The device to be tested increases blood flow to the limb via controlled specific bioelectric signals in sequence for controlled expression of key specific angiogenesis promoting proteins such as VEGF, eNOS, PDGF, HIF 1 alpha, HGF, EGF, IGF-1 and Tropoelastin.  The VascuStim bioelectric stimulator also has controlled signals for recruiting resident autologous stem cells from the patient’s own bone marrow, fat and circulating blood with a homing signal (SDF-1 + PDGF) and controlling proliferation of those recruited cells and their differentiation. It is hypothesized that increasing blood flow and regenerative stem cells to the limb, much as surgical revascularisation, will aid the legs ability to heal and fight infection. After training, it can be used by patients on themselves and is suitable for out-patient therapy.
The sponsor of this study has previously completed limb salvage and diabetic foot ulcer pre-clinical and pilot proof of concept clinical studies in collaboration with collaborating investigators with electrical stimulation with successful results.  Separately they have sponsored limb salvage studies with the injection of adipose derived cells with successful results.
What is unique about this study is the combination of controlled expression of regenerative and angiogenic proteins via bioelectric stimulation and the application of amniotic fluid membranes on the wounds.   
A number of investigators have reported accelerated healing of wounds with the application of amniotic fluid membranes.
The investigators wish to evaluate both the short- and longer-term effects of a bioelectric controlled protein expression stimulator combined with amniotic fluid membranes on diabetic foot ulceration wounds as a therapeutic intervention.
  Eligibility

Ages Eligible for Study: 18 Years and older   (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion criteria
  • 18+ years old
  • Type 2 diabetes on best medical therapy
  • Active foot ulceration, present <3 months Exclusion criteria
  • Pregnancy
  • Pacemaker
  • Metal implants in the legs (below knee)

  Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. 

Please refer to this study by its ClinicalTrials.gov identifier: ***********

Locations
Sponsors and Collaborators
VascuStim a Leonhardt Ventures Co.
Investigators
Principal Investigator:
  More Information

Responsible Party:   VascuStim a Leonhardt Ventures Co.
ClinicalTrials.gov Identifier:
Other Study ID Numbers:
Study First Received:
Last Updated:

Additional relevant MeSH terms:

Diabetic Foot
Foot Ulcer
Diabetic Angiopathies
Leg Ulcer
Skin Ulcer
Diabetic Neuropathies
Vascular Diseases
Cardiovascular Diseases
Skin Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Foot Diseases

Supporting Articles

www.aetna.com/cpb/medical/data/600_699/0680.html

Aetna considers electrical stimulation for the treatment of chronic ulcers in the …. in the treatment of chronic and painful venous leg ulcers in 20 older patients.

Electrical stimulation to accelerate wound healing – NCBI – NIH

https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)
by G Thakral – ‎2013 – ‎Cited by 46 – ‎Related articles

Sep 16, 2013 – Keywords: diabetic foot ulcer, electric stimulation therapy, treatment … delayed wound healing and higher bacterial counts in leg ulcers.

Electrical Stimulation and Cutaneous Wound Healing: A Review of …

https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)
by S Ud-Din – ‎2014 – ‎Cited by 18 – ‎Related articles

Oct 27, 2014 – Keywords: electrical stimulation, electrobiofeedback, wound healing, ….. for the treatment of 47 patients with leg and diabetic foot ulcers [42].

Effect of electrical stimulation on chronic leg ulcer size and appearance.

by PE Houghton – ‎2003 – ‎Cited by 174 – ‎Related articles

Phys Ther. 2003 Jan;83(1):17-28. Effect of electrical stimulation on chronic leg ulcer size and appearance. Houghton PE(1), Kincaid CB, Lovell M, Campbell KE, …

E-Stimulation: An Effective Modality to Facilitate Wound Healing …

www.todayswoundclinic.com/e-stimulation-effective-modality-facilitate-wound-healing

by P Scarborough – ‎Related articles

May 9, 2012 – When it comes to chronic wounds, electrical stimulation (ES), one of …. Effect ofelectrical stimulation on chronic leg ulcer size and appearance.

Effect of Electrical Stimulation on Chronic Leg Ulcer … – Oxford Academic

by PE Houghton – ‎2003 – ‎Cited by 174 – ‎Related articles

Abstract. Background and Purpose. Electrical current has been recommended for use on chronic pressure ulcers; however, the ability of this modality to improve .

A current affair: electrotherapy in wound healing – NCBI – NIH

by J Hunckler – ‎2017

Apr 20, 2017 – The effect of electrical stimulation (ES) has been tested in vitro on different … vascular endothelial growth factor (VEGF) in the blood during the stimulation ….. Asadi MR, Torkaman G. Bacterial inhibition by electrical stimulation. … Evaluation of electrical stimulation for ischemic wound therapy: a feasibility …

The Effect of Microcurrent Electrical Stimulation on the Foot … – J-Stage

by RJ Park – ‎2011 – ‎Cited by 8 – ‎Related articles

stimulation on the foot blood circulation and the degree of pain experienced by diabetes patients. … microcurrent electric stimulation of the foot may be helpful for preventing the … angiogenictherapy9,10). …. 9) Kanno S, Oda N, Abe M, et al.

 

Asadi Angiogenic effects of low-intensity cathodal direct current

Diabetic Foot Ulcers and Their Recurrence

VASCSTIM CLINICAL

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
  1. Able and willing to make the required study visits.
  2. Able and willing to give informed consent and follow study instructions.
  3. 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.