WHY PERFUSION MATTERS
Our larger arteries branch into smaller vessels that terminate in a fine network of capillaries that run through our major organs, our musculature and our soft tissue. Tissue perfusion is the continuous flow of blood cells through these fine vascular networks that provide the oxygen and nutrients our cells need.
A healthy level of tissue perfusion is needed for wound healing. In patients with Peripheral Arterial Disease ("PAD"), foot tissue perfusion levels can fall significantly as a result of atherosclerotic plaque buildup in blood vessels in our legs.
The narrowing of these blood vessels causes a condition called "ischemia", meaning insufficient blood flow. In clinical terms, tissue perfusion has fallen below the oxygenation levels required for cellular metabolism, including wound healing.
When patients with PAD suffer an open wound on the foot, that typically becomes an ischemic chronic wound that cannot heal for months, in some instances even years. The longer the wound remains open, the more likely the chance of infection, which in turn greatly increases the likelihood of tissue necrosis and consequent amputation. Time is of the essence in restoring higher levels of foot tissue perfusion.
The Problem With Current Standard of Care
Poor Diagnostic Tools
The current standard used for frontline diagnosis of foot ischemia is the ankle-brachial index ("ABI"), in which the ankle blood pressure reading is divided by that taken around the upper arm. An ABI <0.9 indicates ischemia.
Unfortunately, it is widely acknowledged that ABI has poor sensitivity of16-20%. This is particularly so for diabetic and chronic renal patients in whom calcified vessels are common, resulting in falsely-elevated ABI readings.
A better diagnostic tool is needed because reliance on pain symptoms is not enough.
"More than half of patients having a major below-the-knee amputation for critical limb ischemia had no symptoms of leg ischemia whatsoever as recently as 6 months prior."
- Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)
In the angio suite, it's always a fine balance between avoiding risk versus being aggressive enough to achieve adequate increase in foot tissue perfusion for wound healing to take place.
Doctors need real-time quantitative perfusion feedback to finetune that balance, and make the right judgment calls while the patient is on-table.
Limited Angio Suite Guidance
PAD patients undergo angioplasty of their leg vessels to improve blood flow to their feet. During these procedures, the doctor inserts a balloon catheter via a small insertion in the groin artery. The catheter is threaded to the site of the vessel lesions (narrowing or occlusions) where the balloon is expanded with saline to widen the vessel lumen. Sometimes stents are inserted as permanent implants within the vessel as a scaffold to keep the lumen open.
These angioplasty procedures often present with multiple lesions in multiple blood vessels, requiring the doctor to make on-table decisions that balance benefit vs risk.
The opening of more lesions, if successful, increases the probability of a good post-operative outcome. On the other hand, each lesion also poses an incremental risk of complications such as vessel dissection. Different tools such as stents, atherectomy devices can be used with varying degrees of complexity, each adding cost to the procedure. Additional factors to be considered include the complexity of below-knee diffuse, calcified disease common in diabetics; any idiosyncrasies in vessel anatomy and collateral flow channels; and the existence of renal issues that may limit the use of X-ray contrast fluid.
In carrying the burden of these important decisions, the doctor has only X-ray angiographic images to guide him. These are useful to locate the precise location of the lesions, but they were never designed for, and are not capable of providing a quantitative perfusion readout. An angiogram can show that a lesion has been opened, but it cannot confirm that the opening of a lesion has led to a rise in foot tissue perfusion at the wound site. As a result, patients may have sub-optimal outcomes, including repeat procedures and/or amputation.
Diabetic Foot Ulcers
A diabetic foot ulcer ("DFU") is an open foot wound that has difficulty healing. Like other chronic wounds, most DFUs stay open for weeks and months, sometimes years.
The challenge in getting the right treatment for DFUs lies in the fact that these can be caused by two different physiological issues: foot ischemia and diabetic neuropathy. Depending on the cause, the treatment is very different.
Ischemic DFUs should be immediately referred to a vascular specialist, and often require either balloon angioplasty or bypass surgery to restore sufficient tissue perfusion before the DFU can heal. In contrast, Neuropathic DFUs do not require vascular intervention because their blood flow is adequate - the wound fails to heal only because the patient keeps walking on it due to the lack of pain sensation in the foot. In these cases, offloading solutions such as shoe inserts or full contact casts can work effectively to take the offending pressure off the wound, which then heals within weeks.
So how do we tell if a DFU is ischemic or neuropathic?
Therein lies the challenge. The current gold standard for frontline diagnosis of ischemia is the Ankle-Brachial Index, which has a real-world sensitivity of 16-20%. (Earlier claims of >90% sensitivity were based on flawed studies in the 1960s, and have been superseded by more recent data correlated against angiographic evidence of foot ischemia.)
ABI is widely appreciated as being a very poor test for diabetic limbs, because patients with diabetics often have calcified blood vessels i.e. the buildup of hard calcified plaque within their leg vessels. Their ankle vessels are incompressible by the blood pressure cuff, and this results in falsely-elevated ABI readings that fall within the healthy range.
The danger of ABI being such a poor frontline test for ischemia is that patients with ischemic DFUs who seek help may be sent home with mere wound dressings upon a "wait and see" approach. If the wound is so highly ischemic that wound healing cannot possibly take place without vascular intervention, such a "wait and see" approach is likely to lead to a downward spiral of events starting with first an increase in wound size, then infection and in the worst cases, amputation.
“…When vascular calcification is present, stenotic disease cannot be detected by the ABI.
….Unmet Needs: Fields of Research For The Future…..Further research should explore potentially easier and faster alternative methods for ABI measurement that would likely be implemented more broadly in primary care.”
“Measurement and Interpretation of the Ankle-Brachial Index: A Scientific Statement From the American Heart Association”, Aboyans et al, Circulation 2012;126:00-00.
“…People seen within two weeks are more likely to be alive and ulcer-free than those seen later. Patients not seen for two months or more were most likely to have severe ulcers..."
The National Diabetes Foot Care Audit 2014-2016, NHS, Diabetes UK, Healthcare Quality Improvement Partnership (HQIP)
The difference between early and late diagnosis and treatment cannot be understated. In this UK audit report reviewing 11,073 patients, 58% experienced severe ulcers and the worst outcomes simply because they waited more than 2 months to seek treatment.
DFUs are more common, and more deadly than you may think.
1. 25% of diabetic patients have at least one foot ulcer over their lifetimes.
2. 50-70% of DFUs recur within 5 years.
3. 15-22% of patients proceed to amputation.
4. Amputation rate is 9 times greater than for foot ulcer patients without diabetes.
5. 70% risk of double amputation in 3-5 years.
6. 47% risk of 5-year mortality after amputation.
In diabetic patients, the peripheral arterial disease is much more likely to be diffuse and complex, and up to 75% of the lesions are below the knee. These lesions are often highly calcified, and at least half of them are likely to be total occlusions and/or more than 10cm (4 inches) long. This type of vessel disease is not as easy to treat in angioplasty, which is why real-time perfusion monitoring is critically needed by the physician in order to facilitate real-time decision-making.
The PEDRA Xauron Perfusion System
The first device to achieve real-time, deep-tissue perfusion monitoring on a quantitative index.*
Granted Breakthrough Device Designation by FDA on January 22, 2021 for treatment of critical limb ischemia.
* Pre-approval product in clinical studies.
Real-time perfusion feedback in <10 seconds.
Up to 4 channels to assess perfusion changes across foot angiosomes.
Portable, and VESA-compatible for use with rolling cart or pole platforms.
Radiolucent sensors integrate seamlessly with angiographic imaging.
Simple user interface approved by physicians and angio suite staff.
Built-in battery permits continuous monitoring from angio suite to recovery room.
Completely non-invasive; no need for contrast or other dye fluids.
Demonstrated Sensitivity To Periprocedural Perfusion Changes
For the first time, with advanced speckle laser technology, we are able to give physicians real-time perfusion feedback that enables them to make the right decisions in the angio suite. This can guide the right decisions to take on more procedural risk, as appropriate, for the sake of avoiding negative patient outcomes.
Improving the Diagnosis of PAD and CLI
Preliminary data indicates 96% Sensitivity In Detecting Critical Limb Ischemia
Early studies demonstrate that our perfusion technology is also able to diagnose critical levels of foot ischemia with high accuracy.
This is vitally important in the diagnosis of Peripheral Arterial Disease ("PAD"), because at least two-thirds of PAD patients are asymptomatic. A large proportion have lost the ability to feel pain due to diabetic neuropathy which renders the foot numb.
While the lack of pain may be seen to be a blessing by some, the unfortunate result is that many individuals with PAD who are at high risk of chronic ischemic foot ulcers are completely unaware of their condition. They therefore fail to take even the simplest precautions such as wearing properly-fitting shoes in order to avoid the onset of a chronic foot ulcer that is difficult to heal, which can greatly reduce the quality of life, and which carries a risk of amputation.
With Pedra’s technology, the doctor can, during the first diagnostic visit, easily and quickly conduct a 5-minute non-invasive test to distinguish between ischemic and neuropathic DFUs. He can immediately direct the severely ischemic patients towards a vascular specialist for appropriate intervention.
At PEDRA , our goal is to drive the move...
Post-op Monitoring: ABI
Away from status quo of failed ABI in the clinic and sub-optimal information in the angio suite.
To precise perfusion monitoring for accurate and consistent tracking of disease progression across the entire care continuum.
Kareen Looi, CEO
MBA (Darden), LLB (NUS)
Kareen is a serial entrepreneur in the field of vascular devices, and was CEO-founder of Setagon, a coronary stent company acquired by Medtronic. She is an LLB, honors graduate from the National University of Singapore, top 2% at the Singapore Bar Examination (PPLC), and was previously an attorney at Drew & Napier in Singapore. She has consulted for government agencies, and spoken on medtech entrepreneurship at Darden (University of Virginia), Singapore-Stanford Biodesign, INSEAD Singapore, National University of Singapore and Singapore Management University.
Whye-Kei Lye, Technology Advisor
BSc, Physics (Caltech), MSc/PhD (Yale)
Whye-Kei is a serial inventor and entrepreneur, and previously CTO-founder of Setagon. He is the Director of Future Healthcare at NTUitive, the innovation arm of the Nanyang Technological University in Singapore. Whye-Kei was the recipient of the Harding Bliss prize for furthering intellectual Life at the Yale school of engineering. He has been an invited speaker and panel member on the topic of entrepreneurship and innovation at Singapore-Stanford Biodesign, National Healthcare Group, and Singapore General Hospital. He is an author of 13 publications and book chapters, and is an inventor on 31 patents and patent applications.
Paul Hayes, CMO
MB ChB, MD
Paul joined PedraTech in 2019, and immediately prior to that was a vascular and endovascular surgeon at Addenbrookes Hospital, NHS, in Cambridge, UK, as well as a Lecturer in Surgery at Cambridge University. He has undertaken a number of first-in-man aortic endovascular implantations, and subsequently trained physicians worldwide in the use of these techniques. In addition to this he has been the Chief/Principal Investigator for many multi-center clinical trials. He sat on the Council of the British Society of Endovascular Therapy for 8 years, was also a member of the Research Committee of the UK Vascular Society Council. He is an author of over 150 papers in peer reviewed journals.
Our Clinical Advisors - Singapore
Steven Kum, MD/MBBS/M.Med(Surg)
Steven is a vascular surgeon with fellowship training in endovascular interventions at Prince of Wales Hospital in Sydney, Park Hospital in Leipzig, Germany, and Universita Vita Salute San Raffaele in Milan, and a certified wound specialist phyisican. In addition to his practice at Mount Elizabeth Novena Hospital in Singapore, Steven serves as a Clinical lecturer at both Yong Loo Lin and Lee Kong Chian Schools of Medicine, and regularly proctors physicians on endovascular procedures in Europe and Asia. He is part of the organizing committee of LINC and VERVE. As a leading expert in percutaneous deep arterialization for no-option CLI, he is the PI or co-PI on many clinical studies and has authorship on numerous articles pertaining to this technique.
Our Clinical Advisors - US
Peter Schneider, M.D.
Dr Schneider is professor of surgery at UCSF. An MD from the Johns Hopkins School of Medicine, he was the founding member and chief of the Division of Vascular Surgery at Kaiser Permanente in Hawaii from 1994-2018, where he developed a Diabetic Limb Treatment Program, and was a pioneer in the build of an endovascular practice. Dr Schneider has served as National Principal Investigator for numerous clinical trials. He is a Fellow of the American College of Surgeons, Distinguished Fellow of the Society for Vascular Surgery, Fellow of the International Society of Vascular Surgery, a past president of Western Vascular Society and has authored several textbooks including Endovascular Skills (4th edn).
Raghu Kolluri, M.D.
Dr Kolluri is the President of the Society for Vascular Medicine. He serves as the Medical Director of Syntropic Core lab at OhioHealth Research and Innovation Institute. As the System Medical Director of Vascular Medicine at OhioHealth, he directs the Vascular Medicine service line and Vascular Laboratories across 12 hospitals in central Ohio. A graduate of the Armed Forces Medical College, India, Dr. Kolluri obtained a Master of Science degree in Physiology from Penn State University, and received Internal Medicine residency training at Riverside Methodist Hospital in Columbus, Ohio, followed by Vascular Medicine fellowship training at the Cleveland Clinic. Previously, as the Director of Vascular Medicine, at Prairie Cardiovascular, Dr. Kolluri established and regionalized vascular laboratories and also established a Wound Core lab. A well-known vascular educator, Dr. Kolluri has been invited to organize and lecture at several cardiovascular conferences across the world. He co-founded The VEINS meeting in 2011. He also founded the SVM Fellows and SVM Advanced Practice Provider review courses.
He serves as a reviewer for several cardiovascular journals and is on the editorial board for Vascular Medicine journal and Annals of Vascular Surgery. His clinical and research interests include non-invasive testing, deep venous thrombosis, critical limb ischemia, and chronic venous disease.
Thomas E. Serena, MD, FACS, FACHM, MAPWCA
Dr. Serena is the founder and medical director of Serena Group, a family of wound, hyperbaric and research companies in the United States. Dr. Serena has been the lead or Principal investigator in over 100 clinical trials and is recognized internationally as an expert in the field of wound healing: He has more than 100 published papers and has given more than 1000 invited lectures throughout the world. He has been a member of the Board of Directors of the Wound Healing Society and served two terms on the board of the Association for the Advancement of Wound Care (AAWC) and is now the President-Elect. He has also been Vice-President of the American College of Hyperbaric Medicine and President of the American Professional Wound Care Association.
Campbell Rogers, MD
Campbell is the Chief Medical Officer of Heartflow Inc which has developed FFRCT technology for non-invasive determination of fractional flow reserve in coronary arteries. From 2006 to 2012, Campbell was concurrently Chief Scientific Officer and Global Head of Research and Development at Cordis Corporation, JNJ. Prior to Cordis, he was Associate Professor of Medicine at Harvard Medical School and the Harvard-M.I.T. Division of Health Sciences and Technology, and Director of the Cardiac Catheterization and Experimental Cardiovascular Interventional Laboratories at Brigham and Women’s Hospital in Boston. He served as Principal Investigator for numerous interventional cardiology device, diagnostic, and pharmacology trials, and has authored numerous journal articles, chapters, and books in the area of coronary artery and other cardiovascular diseases.
Our Clinical Advisors - EU
Vlad Alexandrescu MD, PhD
Vlad is Head of the General, Thoracic & Vascular Surgery Dept. of the Princess Paola Hospital, Luxembourg, Belgium, and a consultant in the Cardio-Vascular and Thoracic Surgery Department of the CHU Sart-Tilman Hospital, University of Liège. He is the leading authority in the angiosome model of perfusion for diabetic neuro-ischemic foot wounds. Author of numerous publications and books, he has organized many surgical, endovascular and multi-disciplinary meetings, specialist training sessions and workshops for the professionals in his field. He is an editorial board reviewer at the Journal of Endovascular Therapy, the Journal of Diabetes and Metabolism and the Journal of Cardiovascular Surgery.
Marco Manzi, MD
Marco is the Director of the Interventional Radiology Unit of the Foot and Ankle Clinic at Casa di Cura Abano Terme in Italy. He is a leading practitioner in the treatment of critical limb ischemia, and developed the pedal plantar-loop technique as a new method for revascularization of foot vessels. Marco has published extensively on peripheral revascularization, and is a recognized voice in major international vascular conference. He has been a member of the scientific board for Abbott Vascular and Clearstream (supplier of angioplasty devices in Ireland), as well as a proctor for Boston Scientific and EV3.
Clinical Case Studies
An advanced prototype of the Xauron device tested in a single-center observational study in Cambridge, UK, demonstrated both safety and ease of use in the angio suite.
Case Study 1: The PEDRA Blood Perfusion Index tracks real-time changes in foot tissue perfusion attendant with balloon inflation and deflation during an angioplasty procedure.
Case Study 2: The large increase in PEDRA Blood Perfusion Index after a successful angioplasty correlates with the observation of a healed ulcer 8 weeks after intervention.
We have achieved insights into the quantitative levels of perfusion that may correlate to wound-healing. These will guide towards larger clinical trials to achieve proof that perfusion guidance at multiple points of care will improve both patient outcomes and achieve healthcare savings via the reduction of ulcer incidence rates, as well as reduction of repeat procedures and amputation-related costs.