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Circularity Healthcare Negotiating $100 million Institutional Funding, Expands Successful D’OXYVA Phase 3 Diabetic Foot Ulcer Treatment Clinical Trials, Expects Fast-Track FDA Approval

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[Los Angeles, CA, July 16, 2019] Circularity Healthcare LLC, developer and manufacturer of transdermal drug delivery and wound healing products, has announced that the company has entered into negotiations with institutional investors to inject up to $100 million in growth capital into the company. The capital is to be used to drive Circularity’s launch of product sales in collaboration with several global multinational partners, with a target of several hundred million dollars. The company’s overarching fundraising goal is to access public equity markets through a multibillion-dollar U.S. IPO in the near future.

Privately-held, Los Angeles-based Circularity Healthcare is capitalizing on its completed successful and expanded Phase 3 clinical studies led by prominent researchers, such as Prof. David Armstrong, Prof. Ito Puruhito and Dr. Felix Sigal, and leading institutions, such as MIT, Airlangga, Harvard, Yale, University of Texas at Arlington, and many others. The clinical studies are expected to lead to the company’s highly anticipated Food and Drug Administration FDA approval as a non-significant risk (NSR) combination drug-device for the rapid and highly effective treatment of diabetic foot ulcers.

These exciting developments come on the heels of the rapidly growing market demand for Circularity’s existing product line with a proven technology, manufacturing and fulfillment base. Circularity has recently begun production of its unique, branded, pharmaceutical-grade platform drug molecules.

Already well positioned as an emerging global biotech and medtech product manufacturer, Circularity is now shifting more focus from its non-regulated wellness and cosmetic products to its premium FDA-approved patented and patent-pending drug solutions. These solutions are delivered with the company’s patented and patent pending, non-invasive and painless, rapid transdermal drug delivery systems. The expanded focus is due to Circularity’s exceptionally positive Phase 3 multicenter, multicountry, and multiyear human clinical trials on diabetic foot ulcers, as well as its overall regulatory development path.

Recently, the company launched sales of MicroScan, a clinical diagnostics tool with an installed base at intensive care units (ICU) in 35 countries worldwide. MicroScan enables Circularity to generate much higher average revenue per customer, while providing highly affordable insights, both for patients and health professionals, into the inner workings and mechanisms of actions underpinning the exceptional clinical outcomes of Circularity’s flagship D’OXYVA product line. Until recently, D’OXYVA was available only under test-marketing programs. Together with the diagnostic tools, health experts implementing D’OXYVA can accurately predict wound healing and other major clinical outcomes, such as achieving healthy blood sugar or blood pressure.

Once D’OXYVA has helped the patient achieve healthy levels in such key areas, physicians typically recommend a less frequent dosing schedule in order to remain symptom-free long-term.

During the past seven years, Circularity has assembled a world-class clinical research, regulatory and legal team comprised of several dozen experts mainly from the U.S. and from several influential European and Asian countries for its comprehensive global market development.

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3 Reasons Why Most Wounds Won’t Heal

There are several connected causes of non-healing wounds. According to figures from the U.S. Centers for Disease Control and Prevention, chronic wounds–injuries that have yet to heal after six weeks–affect some 5.7 American adults. There are many reasons for these non-healing wounds, and understanding each cause is vital to implementing the most effective wound care regimen possible.

Here are three of the more frequent explanations for why many wounds just won’t heal:

 

As Johns Hopkins Medical School pointed out, blood is perhaps the most important component of the entire wound healing process. When an injury occurs, it’s the blood that transports cells to the wound site, which begin rebuilding veins and other important tissue structures. When you have poor circulation, blood cannot move around as quickly, and as a result, wounds take much longer to begin healing. According to Healthline, there are several medical conditions that cause poor circulation, including varicose veins, obesity and chronic ailments like diabetes, peripheral artery disease and Raynaud’s disease. Fortunately, there are just as many ways to improve circulation, like frequent exercise and elevating wounds or limbs in general.

According to the Mayo Clinic, edema occurs when fluid leaks from blood vessels, causing these secretions to accumulate in nearby tissue. The result is a large bump or nodule that is painful and sometimes prone to infection. Edema is usually the result of a number of medications, including several drug therapies geared toward diabetes. Edema can also occur due to a reaction to steroids, anti-inflammatory drugs and even estrogen supplements. Other than being uncomfortable, edema can wreak havoc on the wound-healing process. Due to fluid buildup, the blood vessels and tissue become rigid and immovable, greatly restricting blood flow. This compression cycle can also kill skin patches, which could lead to ulcers.

As a rule, infections can be quite traumatic to the host. Perhaps the biggest effect–one that might surprise some people–is that infections can all but halt the wound healing process. According to St. Luke’s Clinic, an average infection has a number of methods for preventing healthy tissue regeneration. For instance, some infections can extend the length of the inflammatory phase, and that can halt the subsequent stages of wound healing. Additionally, there are strains that can interfere with clotting mechanisms, which in turn causes wounds to continue bleeding. According to a 2010 study from the Journal of Dental Research, the two most damaging strains of bacteria are pseudomonas aeruginosa and staphylococcus.

When it comes to handling chronic wounds, patients need advanced wound care products to prevent infection and create a sustainable healing environment; that’s why so many patients turn to Advanced Tissue when they experience most chronic wounds. As the nation’s leader in the delivery of specialized wound care supplies, Advanced Tissue ships supplies to individuals at home and in long-term care facilities.

 

Ref: https://advancedtissue.com/2016/02/3-reasons-why-most-wounds-wont-heal/

HOW D’OXYVA CAN HELP?

Clinical studies with D’OXYVA®  (deoxyhemoglobin vasodilator) have shown extraordinary results for the role of transdermal noninvasive wound care using ultra-purified, nontoxic, FDA-cleared molecules, such as CO2especially when all other approaches failed.

In an ongoing multiyear, multi-country, multicenter, randomized clinical trial on patients with diabetic foot ulcers, D’OXYVA has demonstrated speeding up diabetic wound healing and ultimately wound closure to an average of 5 weeks**.

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Anesthesia, Microcirculation, and Wound Repair in Aging

Abstract

Age-related changes in skin contribute to poor wound healing after surgical procedures. Changes in skin with age include a decline in thickness and composition, a decrease in the number of most cell types, and diminished microcirculation, the process that provides tissue perfusion, fluid homeostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause further disruption of the microvasculature of aged skin; however, perioperative management can be modified to minimize damage to aged tissues. Judicious use of fluids, maintenance of normal body temperature, pain control, and increased tissue oxygen tension are examples of adjustable variables that support microcirculation. Anesthetic agents influence microcirculation in a number of ways, including cardiac output, arterial pressure, and local microvascular changes. The authors examined the role of anesthetic management in optimizing microcirculation and potentially improving postoperative wound repair in older persons.

Aged skin is at increased risk of poor postoperative wound healing. Changes in the cutaneous microcirculation with aging contribute to this risk. This review examines the role of anesthesia management in microcirculatory function.

SURGICAL wound repair is a major problem in the older population, who are at increased risk of wound dehiscence and infection. As a specific example, surgical site infections (SSIs) are common (approximately 500,000 cases annually in the United States), lead to worse patient outcome (patients who develop SSI are twice as likely to die), and are an enormous economic burden (1–10 billion dollars annually). Many factors contribute to age-related changes in skin5 and subsequent vulnerability to impaired wound healing and infection. Changes in skin with age (fig. 1) include a decline in epidermal and dermal thickness and composition, as well as a decrease in the number of most resident cell types. The dermal–epidermal junction is flattened and the microcirculation is diminished. The latter is defined as blood flow through arterioles, capillaries, and venules and is the key system that affects the entire skin surface. In the aging patient, the microcirculation in the skin is reduced by 40% between the ages of 20 and 70 yr. The microcirculation provides tissue perfusion, fluid hemostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause disruption of the microcirculation in the skin as manifested by local edema resulting from vasodilation and increased vascular permeability.

Fig. 1.
Numerous changes in skin with age contribute to impaired wound healing.
art1.png

 

Perioperative management can be modified to optimize the microcirculation. Measures that support the microcirculation include careful use of fluids, normothermia, pain control, and smoking cessation. Factors that can be influenced by intraoperative management (judicious use of fluids, maintenance of normal body temperature, pain control, and increased tissue oxygen tension) have been suggested to be beneficial as well. Most anesthetic agents also influence the microcirculation: a reduction in cardiac output and arterial pressure decreases flow in the microcirculation, whereas anesthetic-induced local microvascular changes and vasodilatation can increase perfusion. Optimization of these variables plays an important role in enhancing the microcirculation in all patients, but is especially relevant if modifications could improve postoperative wound healing in the older population.

In this review, we will use skin as a representative organ to describe age-related changes that negatively affect the microcirculation and have subsequent impacts on wound healing and the incidence of postoperative infection. We will then examine the role of anesthesia management in minimizing detrimental effects on the microcirculation. A greater understanding of these variables could promote improvements that lead to better outcomes with respect to wound repair in older patients.

Summary of Wound Repair and Aging

It has been nearly a century since it was noted that the rate of cutaneous scar formation after a wound is inversely related to the age of the patient. Four decades ago, it was observed that older age was associated with an increased risk of postoperative disruption of the surgical wound, leading to higher mortality. Recent data suggest that in patients older than 65 yr, development of SSI is associated with a two-fold increase in cost and a staggering four-fold increase in mortality.

Wound healing ensues via a sequential chain of events (with variable overlap) that includes inflammation, tissue formation, and remodeling (fig. 2). Circulating factors have a pivotal role in each of these phases. Accordingly, as we will discuss below, immediate changes in the microcirculation influence each stages of the wound-healing response in aging. As human data is lacking, we have taken data from established animal models of aging. Although animal models are not uniformly predictive of responses in human tissues, several animal models of wound healing are generally accepted.

Fig. 2.

The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.

art2.png

Summary

Nearly every anesthesiologist who provides care to adults will participate in the care of geriatric patients. A growing older population is undergoing surgical procedures that are increasing in number and complexity. Poor healing of surgical wounds is a major cause of morbidity, mortality, and substantial economic burden. Wound healing is dependent on the microcirculation that supplies the incision area. Measures that support the microcirculation during the perioperative period have a profound effect on wound healing. Some measures such as maintenance of normal body temperature and control of postoperative pain are supported by ample evidence and have been implemented in routine clinical care. Other measures, for example, the choice of anesthesia technique and use of opioids are supported by basic research but need further clinical studies. A better understanding of the effect of aging and anesthesia on the microcirculation can potentially assist in improving postoperative wound repair, thereby benefiting a growing older population.

The Surgical Context of Wound Repair and Aging

Measures that support the microcirculation improve wound repair, thereby reducing the risk of postoperative dehiscence and infection.52General preoperative measures such as smoking cessation and optimal management of comorbid medical conditions have been reviewed in other contexts.53,54 For the purpose of this review, we will focus on interventions in the perioperative setting.

Oxygen Administration

Wound healing is dependent upon adequate levels of oxygen.55 Oxygen interacts with growth factor signaling and regulates numerous transduction pathways necessary for cell proliferation and migration.56 It is also an indispensable factor for oxidative killing of microbes.57 Consequently, the effects of oxygen tension on the outcome of surgical wounds have been best studied in the context of postoperative infection. Resistance to surgical wound infection is presumed to be oxygen dependent—with low oxygen tension viewed as a predictor of the development of infection,56 particularly when subcutaneous tissue oxygenation (measured by a polarographic electrode) decreases to less than 40 mmHg.58

In two recent meta-analyses, one found that perioperative supplemental oxygen therapy exerts a significant beneficial effect on the prevention of SSIs,59 whereas the other suggested a benefit only for specific subpopulations.60 Although most authors suggest that supplemental oxygen during surgery is associated with a reduction in infection risk,61,62 others propose it may be associated with an increased incidence of postoperative wound infection.63Notably, in the latter report, the sample size was small and there was a difference in the baseline characteristics of the groups. A prospective trial randomizing patients to either 30 or 80% supplemental oxygen during and 2 h after surgery did not find any difference in several outcome measures including death, pulmonary complications, and wound healing.64 Of note, the administration of oxygen to aged subjects may be limited by the finding that although arterial oxygen tension did not decrease with age, there was reduced steady-state transfer of carbon monoxide in the lungs.65 This indicates that oxygen transport could be diffusion-limited in older subjects, especially when oxygen consumption is increased. Furthermore, longitudinal studies of five healthy men over 3 decades showed impaired efficiency of maximal peripheral oxygen extraction,66 suggesting that tissue oxygen uptake is reduced in the aged subjects.67 This likely reflects a decrease in the number of capillaries as well as a reduction in mitochondrial enzyme activity.68 Animal models (rabbit69 and mouse69,70 ) have suggested that aging and ischemia have an additive effect on disruption of wound healing. Consequently, the potential benefit of increasing tissue oxygen tension during surgical wound repair in older patients should be further evaluated.

Reference: http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1917910

 

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The Agony of the Feet as You Get Older

Making foot care a priority as you get older is important for maintaining a healthy and active lifestyle.

WHILE PEOPLE OFTEN PAY attention to how their feet look once sandal season comes around, they give their feet little TLC the rest of the year. Meanwhile, we pound our feet on the pavement or place three to four times our body weight on them when we jog, and we often subject our feet to tight or poorly-fitting shoes or precarious heels. Given these stresses and strains, it’s a wonder the human foot – with its 26 bones, 33 joints and complex matrix of ligaments, tendons, and muscles – doesn’t launch a full-scale rebellion.

But sometimes it does, especially as we get older. Indeed, a study in a 2016 issue of Maturitas found that foot pain affects 1 in 4 adults after age 45, and it’s at least somewhat disabling in two-thirds of those cases. Even worse, foot pain in older adults is associated with a 62 percent increased risk of recurrent falls, according to a study in a 2017 issue of Gerontology. “As we get older, our muscles and tendons lose elasticity, which can contribute to foot pain,” says Beth Gusenoff, a podiatric surgeon and clinical assistant professor in the University of Pittsburgh Medical Center’s department of plastic surgery.

It’s important to make your foot health a priority, especially as you get older, because “a healthy foot is a catalyst for mobility and a healthy lifestyle,” Gusenoff says. “Your feet really are your base of support.”

Here are six things you may not know about your aging feet, but should.

Obesity can increase your risk of suffering from foot pain. A study in a 2017 issue of the journal Obesity Research & Clinical Practice found that as people’s body mass index (or BMI) increases from the normal range to obesity, so do the odds that they will have foot pain as they get older; this is true for men and women. With excess weight on the body, “the foot can’t handle the mechanical load that’s being put on it,” Gusenoff says.

Unfortunately, obesity can create a vicious cycle where excess weight increases the risk of foot pain, which makes people less likely to engage in weight-bearing physical activities, which can lead to more weight gain, and so on, notes Dr. Clifford Jeng, medical director of the Institute for Foot and Ankle Reconstruction at Mercy Medical Center in Baltimore. Consider this extra incentive to shed excess pounds.

Loss of fat in the feet can make you more susceptible to foot pain. We’re all born with a certain amount of fat under our feet, especially under the heels and the balls of our feet, which allows for shock absorption. “As we age, the fat padding under our feet can atrophy – some people’s gets thinner more rapidly than others,” Jeng explains. Overtraining and then getting cortisone injections to reduce pain and swelling in the feet can accelerate the fat pad loss. When this happens, people often complain that it feels like they’re walking on hard rocks or marbles, which can lead to pain and flattening of the feet. What’s more, “losing the fat pad can make you more susceptible to stress fractures, bruised bones and balance problems as you get older,” Gusenoff notes. Since fat can’t be transplanted from other parts of the body – at least not yet – “the only thing that we can do is to supplement the fat pad with external cushioning like silicone,” Jeng says. You can buy insoles or gel pads to put in your shoes wherever you need the extra padding, including under your heel, under the ball of your foot or next to a bunion.

Compromised blood flow to the feet can cause or worsen foot pain. Various factors can affect the quality of blood flow to the feet, including whether you smoke or have diabetes, peripheral neuropathy or blood clots. Poor circulation to the feet is a problem because “diminished blood flow may manifest itself as frank pain when the soft tissues are not being perfused with enough circulation,” notes Tim Swartz, Chief of Podiatry at Kaiser Permanente’s Mid-Atlantic region. “Wound and tissue healing can also be a problem if there is compromised blood flow” to the feet. That’s why it’s essential to tell your doctor about any numbness or tingling you have in your feet, as well as any chronic diseases, such as diabetes, arthritis or vascular disorders.

Different foot ailments become more common with age. Bunions, hammertoes, fungal infections, corns and calluses can occur at any age. Meanwhile, certain foot ailments become more common as people get older. These include plantar fasciitis (pain in the bottom of the heel that occurs when the band of tissue that supports the arch becomes irritated and inflamed), posterior tibial tendonitis (in which the tendon that attaches the calf muscle to the bones on the inside of the foot becomes torn or inflamed), Achilles tendinitis and big toe arthritis, Jeng says. Persistent pain or swelling in the foot, especially when accompanied by compromised mobility, should warrant a visit to your doctor.

“Sometimes foot pain in the aging population is dismissed as due to age and tired feet, but there may be a true underlying cause of the pain that can be treated,” Gusenoff says. “Improving pain and keeping a patient mobile and active can be a catalyst for healthier living and a better quality of life.” She recommends doing basic stretches for your Achilles tendon, foot circles and balance exercises, such as toe and heel raises or standing on one foot. In terms of cardio workouts, cycling and swimming are easier on the feet because they’re not weight-bearing activities.

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Optic Imaging to Understand the Healing of Diabetic Wounds

A team of North American researchers demonstrated a label-free and more direct way to observe and quantify microvascular and metabolic healing mechanisms, as well as the biological response to a topical treatment, utilizing a multimodal microscope equipped with optical coherence tomography (OCT) and fluorescence lifetime imaging microscopy (FLIM).

Diabetes affects more than 29 million people in the United States, and this number is projected to double or triple by 2050. This disease causes many physiological complications, such as diabetic foot ulcers. Such impaired wound healing in diabetic patients is caused by a variety of physiological abnormalities, one of which is poor microcirculation, which is essential for normal wound healing.

A team from the Beckman Institute for Advanced Science and Technology in the USA investigated the healing mechanisms of a novel topical ointment for diabetic wounds that is capable of promoting angiogenesis by inducing local physiological conditions that mimic hypoxia. Angiogenesis has a crucial role in many diseases and physiological responses, including wound healing. The topical treatment that was investigated mimics hypoxia via inhibition of prolyl hydroxylase, a key regulator of hypoxia-inducible factor (HIF).

Currently, characterizations of wound healing and associated treatments rely heavily on visual inspection, digital photography, and ex vivo analysis. In recent years, several optical imaging techniques have proven beneficial in observing key biological events, both in vivo and ex vivo, in processes such as wound healing, at resolutions unparalleled by conventional techniques.

In this study, phase-variance OCT (PV-OCT) and FLIM were utilized to track the regeneration of the microvasculature network and the change in cellular metabolic activity, respectively, in wounded and healing skin in diabetic (db/db) mice.

PV-OCT imaging and analysis showed that the ear wounds in mice treated with this angiogenesis-promoting agent demonstrated a significant increase in vessel density. While additional studies are required to further understand the larger number of complex healing mechanisms involved in the skin wound-healing process, the cross-modality correlation between PV-OCT and FLIM presented in the study successfully relates the increase in vasculature density to the relative changes in cellular metabolism in living animals.

“Insights gained in these studies could lead to new endpoints for evaluation of the efficacy and healing mechanisms of wound-healing drugs in a setting where delayed healing does not permit available methods for evaluation to take place” concludes team member Stephen A. Boppart.

Reference: https://www.advancedsciencenews.com/optic-imaging-to-understand-the-healing-of-diabetic-wounds/

How can D’OXYVA help?

In an ongoing multiyear, multi-country, multicenter, randomized clinical trial on patients with diabetic foot ulcers, D’OXYVA has demonstrated speeding up diabetic wound healing and ultimately wound closure to an average of 5 weeks**.

In addition, D’OXYVA eliminated pain and improved quality of life factors such as sleep, appetite, and mood in just a week in 100% of subjects. No adverse events of any kind were reported during, and years after, the studies.

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