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A D A C L I N I C A L C O M P E N D I A S E R I E S
2022
CONTRIBUTING AUTHORS
ANDREW J.M. BOULTON, MD, DSC (HON), FACP, FRCP
Professor of Medicine, University of Manchester, Manchester, U.K., and Visiting Professor of Medicine, University of Miami Miller School of Medicine, Miami, FL
DAVID G. ARMSTRONG, DPM, MD, PHD
Professor of Surgery, Keck School of Medicine of the University of Southern California and Director, Southwestern Academic Limb Salvage Alliance (SALSA), Los Angeles, CA
MAGNUS LÖNDAHL, MD, PHD
Associate Professor of Endocrinology, Department of Clinical Sciences, Lund University, Lund, Sweden, and Medical Head, Department of Endocrinology, Skane University Hospital, Lund, Sweden
ROBERT G. FRYKBERG, DPM, MPH
Adjunct Professor, Midwestern University, Glendale, AZ
FRANCES L. GAME, MD
Consultant Diabetologist, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, U.K.
MICHAEL E. EDMONDS, MD, FRCP
Consultant Diabetologist, King’s College Hospital NHS Foundation Trust, and Honorary Professor of
Diabetic Foot Medicine, King’s College, London, U.K.
DENNIS P. ORGILL, MD, PHD
Professor of Surgery, Harvard Medical School; Medical Director, Wound Care Clinic, Brigham and Women’s Hospital, Boston, MA
KIMBERLY KRAMER, MPH
Research Project Manager, Division of Plastic Surgery, Brigham and Women’s Hospital, Boston, MA
GEOFFREY C. GURTNER, MD, FACS
Johnson & Johnson Distinguished Professor of Surgery and Professor (by courtesy) of Materials Science and Engineering, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA
MICHAEL JANUSZYK, MD, PHD
Harry R. Hagey Research and Clinical Fellow, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA
LORETTA VILEIKYTE, MD, PHD
Senior Lecturer in Medicine, University of Manchester, Manchester, U.K., and Visiting Research Associate Professor of Medicine, University of Miami Miller School of Medicine, Miami, FL
New, Evidence-Based Therapies for Complex Diabetic Foot Wounds is published by the American Diabetes Association, 2451 Crystal Drive, Arlington, VA 22202. Contact: 1-800-DIABETES, professional.diabetes.org.
The opinions expressed are those of the authors and do not necessarily reflect those of the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.
©2022 by American Diabetes Association. All rights reserved. None of the contents may be reproduced without the written permission of the American Diabetes Association.
Print: ISSN 2771-6872
Online: ISSN 2771-6880
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Cover images credit: spline_x/Shutterstock
ABBREVIATIONS
ABI Ankle-brachial index
ADA American Diabetes Association
ATA Absolute atmosphere
CDO Continuous delivery of oxygen
COVID-19 Coronavirus disease 2019
D Day
DFO Deferoxamine
DFU Diabetic foot ulcer
FDA U.S. Food and Drug Administration
HBOT Hyperbaric oxygen therapy HIF-1α Hypoxia-inducible factor 1α ITT Intention-to-treat
IWGDF International Working Group of the Diabetic Foot
M Month
MMP Matrix metalloproteinase
NOSF Nano-oligosaccharide
NPWT Negative pressure wound therapy
OR Odds ratio
PAD Peripheral artery disease PDGF Platelet-derived growth factor PO2 Partial pressure of oxygen RCT Randomized controlled trial RWD Real-world data
RWE Real-world evidence
TBI Toe-brachial index
TcPO2 Transcutaneous oxygen pressure
TLC Technology lipido-colloid
TOT Topical oxygen therapy
UT University of Texas
UTAUT Unified Theory of Acceptance and Use of Technology
VEGF Vascular endothelial growth factor
W Week
New Evidence- Based Therapies for Complex Diabetic Foot Wounds
Andrew J.M. Boulton, MD, DSc (Hon), FACP, FRCP1,2
David G. Armstrong, DPM, MD, PhD3,4 Magnus Löndahl, MD, PhD5,6
Robert G. Frykberg, DPM, MPH7 Frances L. Game, MD8
Michael E. Edmonds, MD, FRCP9 Dennis P. Orgill, MD, PhD10 Kimberly Kramer, MPH10 Geoffrey C. Gurtner, MD, FACS11 Michael Januszyk, MD, PhD11 Loretta Vileikyte, MD, PhD1,2
ABSTRACT | This publication is the third in a series of American Diabe- tes Association compendia on the diabetic foot. Previous installments focused on the diagnosis and management of diabetes foot complica- tions and infections. Here, the authors turn their attention to the latest evidence-based therapies for diabetic foot ulcers (DFUs). The mono- graph begins with an overview of the current state of diabetic foot care, as well as a brief history of oxygen therapy for the treatment of DFUs. The most recently published evidence-based data concern topical oxy- gen therapies, and these are described in detail. Subsequent sections summarize the evidence published mainly in the past decade for spe- cific treatments, including autologous leucocyte, platelet, and fibrin multilayered patches; sucrose octasulfate dressings; and negative pres- sure wound therapy. The authors discuss the evidence related to the
use of new therapies specifically for the treatment of neuropathic and
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neuroischemic lesions. They then look to the future at new treatment approaches in the development pipeline, as well as the emerging role of wearable technologies such as digitally connected insoles and socks in preventing DFU recurrence. Throughout the compendium, the authors present their view of current and forthcoming treatment options and iden- tify areas worthy of additional research in the years ahead.
fter the outstanding success of two previous American Diabetes Association (ADA) compendia on the diabetic foot—Diagnosis
and Management of Diabetic Foot Complications (1) and Diagnosis and Management of Diabetic Foot Infections (2)—the Association asked us to proceed with a third volume.
At the time of writing, the International Diabetes Federation had just published the 10th edition of its IDF Diabetes Atlas (3), which, in many ways, makes for depressing reading. The past 2 years have seen a 16% increase in the global prevalence of diabetes, with one in 10, or >537 million, adults now having the disease. However, depressing though these data are, they do not take into account the impact the cur- rent global coronavirus disease 2019 (COVID-19) pandemic will like- ly have on the worldwide prevalence of diabetes and its complications. Our pessimism regarding this possible impact is supported by a recent study from the United Kingdom which, using A1C as a surrogate, esti- mated the effect of the pandemic on diabetes diagnosis and manage- ment (4). An 80% reduction in A1C testing was reported in April 2020;
1University of Manchester, Manchester, UK 2University of Miami Miller School of Medicine, Miami, FL
3Keck School of Medicine of the University of Southern California, Los Angeles, CA 4Southwestern Academic Limb Salvage
Alliance (SALSA), Los Angeles, CA
5Department of Endocrinology, Skane University Hospital, Lund, Sweden 6Department of Clinical Sciences, Lund
University, Lund, Sweden
7Midwestern University, Glendale, AZ 8University Hospitals of Derby and Burton NHS Foundation Trust, Derby, U.K.
9King’s College Hospital, London, U.K.
10Division of Plastic Surgery, Brigham and Women’s Hospital, Boston, MA 11Department of Surgery, Division of Plastic
and Reconstructive Surgery, Stanford
University School of Medicine, Stanford, CA
Address correspondence to Andrew J.M. Boulton, [email protected], and David G. Armstrong, [email protected].
©2022 by the American Diabetes Association, Inc.
in the first 6 months of the pan- demic, an estimated 1.4 million A1C tests were missed for routine monitoring of glycemic control, and >5 million more tests were missed for the diagnosis of diabe- tes. Thus, we fear a tsunami of di- abetes and its late complications in the next decade.
Sadly, despite recent prog- ress in prevention, diagnosis, and management, these recent devel- opments will likely result in an in- creased incidence of diabetic foot ulcers (DFUs). Thus, the need for good, evidence-based, efficacious treatments for chronic DFUs is more important than ever.
Previously, we reported on a renaissance in diabetic foot care, with new evidence-based treatments (1,2). A number of new therapies are now avail- able, with efficacy supported by well-designed, randomized con- trolled trials (RCTs).
Although there is a long history of the use of oxygen therapies for chronic DFUs, hyperbaric oxygen therapy (HBOT), which is most commonly used in the United States, has little evidence to sup- port its use, and almost all RCTs of this treatment have been neg- ative (5). However, recent trials of topical oxygen therapy (TOT) for DFUs have been encourag- ing (6,7). Thus, we asked our ex- pert writing group first to review the history of oxygen therapies in the diabetic foot and then to dis- cuss the increasing evidence that TOT can accelerate the healing of chronic DFUs.
Other new, evidence-based therapies for DFUs include autologous leucocyte, platelet, and fibrin multilayered patch- es for hard-to-heal ulcers and sucrose octasulfate dressings for hard-to-heal neuroischemic ul-cers (8,9). This treatise includes reviews of both of these new therapies by members of our au- thor group (F.L.G. and M.E.E.) who participated in the clinical trials of the respective agents. Additionally, the use of nega- tive pressure wound therapy (NPWT), which is also support- ed by evidence from RCTs, is re- viewed. The final two sections of this compendium explore pu- tative new, evidence-based ther- apies for DFUs that are in the pipeline and, most important- ly, how we might engage digital technology and other aids to fa- cilitate the prevention of DFU recurrence.
History of Oxygen Therapy for the Treatment of DFUs
Oxygen is essential for energy production and tissue survival in humans. However, it is not only a prerequisite for aerobic cell me- tabolism. Reactive oxygen spe- cies such as hydrogen peroxide and superoxide are crucial in the oxidative killing of bacteria. They also serve as cellular messen- gers to stimulate key processes in wound healing, including cell mo- tility, cytokine action, and angio- genesis. Inflammatory reactions and reparative processes, includ- ing cell proliferation and collagen synthesis following tissue inju- ries such as DFUs, increase oxy- gen requirements. If the need for oxygen is beyond the body’s deliv- ery capacity to the affected area, the healing process will be com- promised, increasing the risk of severe infections and gangrene. Although the role of oxygen in ul- cer healing is not yet completely understood, many experimental and clinical studies have shown DFU healing to be impaired in hy- poxic conditions. In diabetes, macrovascular and microvascular disease contribute to impaired blood circulation in the lower extremities. It is manda- tory to evaluate peripheral circu- lation early in the course of DFU treatment, as an open or endovas- cular procedure might restore the vascular and oxygen-delivering capacity to a level conducive to ulcer healing. Macrovascular dis- ease tends to occur at a younger age and engages more distal ves- sels in people with diabetes. Mi- crovascular dysfunction is an even more treacherous compan- ion to diabetes, as it progress- es over a long time and engages all organ systems. The conse- quences of the capillary basement membrane thickening with en- dothelial hypertrophy, increased permeability, and decreased responsiveness to environmen- tal and physical changes are fre- quently present in people with DFUs. These changes result in di- minished blood flow, decreased oxygen tension, tissue edema, and subsequent capillary rarefaction. Because the rate of oxygen deliv- ery is inversely proportional to the square of the distance and di- rectly proportional to the partial pressure of oxygen (Po2) at the initial point at the capillary, these consequences lead to reduced ox- ygen delivery capacity and in- creased risk of clinically signifi- cant ischemia.
Accordingly, as a rational con-sequence of the observation that the lack of oxygen decreases ul- cer healing, applying oxygen ei- ther topically or systemically has a long history, and several meth- ods have been implemented to in-crease DFU healing by modifying oxygen concentration.
In 1775, Joseph Priestley test- ed his discovered dephlogisticat- ed air (later called oxygen by La- voisier) on himself and wrote, “The feeling of it in my lungs was not sensibly different from that of common air, but I fancied that my breast felt peculiarly light and easy for some time afterwards” (10,11). The first investigations on the efficacy of oxygen in treat- ing disease occurred from 1798 to 1800 at the Pneumatic Institu- tion in Bristol, U.K., and it is pos- sible that this is where the first ox- ygen inhalation treatment for a DFU was given. Apart from that, many of the techniques used in modern oxygen therapy, including corrugated noncrushable breath- ing tubes, mouthpieces, and the mass production of gases, orig- inate from this early work (12). These early rational years were followed by dark ages when inter- mittent oxygen treatment became a panacea and was brought to the market by charlatans and profi- teers. This era climaxed in 1869, when an article in The Lancet ad- vocated oxygenated bread and wa- ter (13). The early 1890s were a new dawning for oxygen therapy, during which continuous inhaling was successfully introduced in people with pneumonia (14). The origin of rational systemic med- ical oxygen use can be dated to early 1917, when John Scott Hal- dane published an article titled “The Therapeutic Administration of Oxygen” (15). Oxygen was added to the ar-mamentarium of DFUs some 50 years later. Anecdotal sto- ries of reduced infection and hastened healing resulting from daily flooding of DFUs with oxygen in hospitalized patients might be considered the origin of TOT (A. Nilsson, personal com- munication). TOT, the adminis- tration of oxygen applied topi- cally over injured tissue by either continuous or pressurized deliv- ery, was introduced in the mid- 20th century (16). A bag, boot, or extremity chamber is placed around the DFU, sealed tight- ly to prevent leakage, and at- tached to an oxygen delivery de- vice or tank. In TOT, oxygen is given with either constant or cyclical pressure. If not contin- uous, a typical session lasts 90 minutes, and the therapy is giv- en three to five times per week. In animal models, TOT has been shown to increase wound tissue Po2 levels tenfold, accompanied by increased vascular endothe- lial growth factor (VEGF) lev- els, signs of improved angiogen- esis, and better collagen quality. Until recently, clinical evidence supporting TOT in the healing of DFUs has been scarce, but in recent years, several positive, well-designed trials of TOT have been published and are discussed in detail below.
Parallel to the introduction of TOT, Brummelkamp et al. (17) reported beneficial ef- fects of HBOT for infected isch- emic leg ulcers, and in 1979, Hart and Strauss (18) published the first DFU study. HBOT is a short-term, high-dose oxygen inhalation and diffusion thera- py that is delivered systemically through airways and blood and achieved by having the patient breathe concentrated oxygen at a pressure >1 absolute atmosphere (ATA). The treatment is given in hyperbaric chambers. Patients with DFUs are usually treated once daily for 80–90 minutes at 2.0–2.5 ATA (the pressure 10–15m below sea surface), on 5 days per week for 6–8 weeks. The rationale for HBOT is to restore abnormal tissue oxygen tension by applying basic physi- cal gas laws. Compared to normo- baric air-breathing, the volume of dissolved oxygen in plasma and tissue during an HBOT ses- sion increases 20-fold, allowing survival without erythrocytes. In cell and animal models, HBOT has been shown to improve leu- kocyte function, enhance neo- vascularization, reduce edema, downregulate inflammation, and enhance granulation tissue for- mation. Altogether, 210 patients with hard-to-heal ulcers without the need for or possibility of vas- cular intervention at the time of randomization have been includ- ed in RCTs reporting long-term follow-up of at least 1 year (19– 21). Of the patients receiving HBOT, 63% healed compared to 20% of those in control groups. Two RCTs that included patients with severe peripheral artery disease (PAD) and allowed for early vascular intervention have been published. In 68 hospital- ized patients with severe infec- tion or PAD, Faglia et al. (22) demonstrated a statistically sig- nificant reduction in major am- putation of 9 versus 33% in favor of HBOT, although this trial lat- er came under criticism. More recently, Santema et al. (23) showed a nonsignificant 45% re- duction in major amputations of 12 versus 22% during the first year after HBOT. Howev- er, this study exemplified one of the main problems with HBOT studies in that it was underpow- ered, with pre-terminated en- rollment when only 53% of the preplanned 226 participants had been randomized.
Robust evidence is lacking for the selection of a treatment reg- imen leading to optimal thera- peutic benefit (i.e., hyperbaric pressure level, duration of treat- ment sessions, number of HBOT sessions, and—not least—timing of HBOT). Transcutaneous oxy- gen pressure (TcPo2), in contrast to ankle-brachial index (ABI) or toe-brachial index (TBI), seems to be helpful to predict treatment outcome, with the increment during hyperbaric conditions be- ing the best predictor. Further- more, the cost of HBOT, espe- cially in the United States, has resulted in questioning of its use- fulness. Finally, there have been a number of negative studies on HBOT in DFUs in the past two decades, although these, too, re- ceived much criticism (5).
In the 21st century, new meth- ods to increase ulcer oxygen- ation have focused on dress- ings and local treatments such as a topical spray containing purified porcine hemoglobin to facilitate oxygen transport from the surface to the bottom of the wound bed. The clinical effica- cy of these methods remains to be proven. Future possible noteworthy methods include an alginate gel containing oxygen- storing droplets and a gel con- taining microspheres with hy- drogen peroxide.
History repeats itself. Mirror- ing the use of oxygen a century earlier, HBOT was, during parts of the 20th century, promoted as a cure for almost any disease, of- ten without supporting evidence beyond single case reports. These issues have affected the reputa- tion of the therapy. Hypoxia im- pairs the healing of DFUs. Both TOT and HBOT can remedy tis- sue hypoxia, and several RCTs have shown their potential for im- proving DFU healing. However, rigorously designed, adequately powered, and well-executed RCTs are needed to accurately validate the potential benefits of these and other oxygen concentration– increasing therapies in the plausi- ble future DFU armamentarium.
New, Evidence-Based Therapies for DFUs
TOPICAL OXYGEN THERAPY
TOT has been misunderstood and sometimes maligned since it was first described in 1969 (16). An- other, later article (24) reported on a poorly designed trial of top- ical “hyperbaric” oxygen therapy that demonstrated no significant differences in healing chronic DFUs after only 2 weeks of treat- ment compared to best-practice standard care treatment in 28 hospitalized patients. Nonethe- less, TOT continued to be used clinically throughout the ensuing decades, albeit with primarily ob- servational studies that suggested positive outcomes in a variety of wounds (25–29).
Oxygen is obviously essential for life itself, and it is no less es- sential for wound repair, being a necessary co-factor for several oxygen-dependent enzymes that are crucial in the wound healing cascade (Table 1) (26). The over- arching and long-debated con- cern is whether topically adminis- tered oxygen can actually promote wound repair. Despite the prem- ise by proponents of HBOT that TOT could not meaningfully af- fect wound healing, clinical com- parative studies in both DFUs and venous leg ulcers have suggested otherwise (27,29).
TABLE 1 Role of Oxygen in Wound Healing
| OXYGEN-DEPENDENT PRODUCT | ENZYME OR SUBSTRATE | FUNCTION | CYTOKINE, CELL MEDIATORS, OR CELLULAR/TISSUE EFFECT |
PDGF, platelet-derived growth factor. Adapted from ref. 32.
A particularly compelling ani- mal study in 2005 (30) augment- ed many clinical observations by demonstrating histological, bio- chemical, and regenerative advan- tages of using topically adminis- tered oxygen compared to ambient air as a control treatment. Recog- nizing that more rigorous studies were required to provide the evi- dence necessary to fully embrace this therapy as a proven wound healing adjunct, multiple formal clinical trials were initiated and have been reported in the past decade (6,31–33).
TOT Delivery Devices There are three general types of delivery systems for TOT, each of which allows for ambulato- ry or home-based treatment: 1) those generating continuous de- livery of oxygen (CDO) at negli- gible pressures, 2) low constant pressure delivery in a contained chamber, and 3) higher cyclical- ly pressurized and humidified de- livery in a contained extremity chamber (Table 2) (32,34). CDO devices apply topical continu- ous diffusion of nonpressurized oxygen through small cannulas to semi-occlusive or proprietary wound dressings. Small, portable, battery-powered electrochemical oxygen generators supply a con- tinuous flow of pure oxygen over the wounds 24 hours per day at a flow rate of up to 15 mL/hour.
The low-constant-pressure (22- mmHg) device uses an oxygen concentrator to deliver oxygen in a simple plastic boot that is placed over the extremity with the ulcer. The third system dif- fers from the other devices in being a multimodality approach that applies cyclically pressur- ized (10–50 mbar) oxygen within a disposable extremity chamber connected to a controller unit and oxygen concentrator. Humidity can be added to this system if re- quired. The higher Po2 produced especially by the latter devices results in a larger pressure gra- dient that promotes the diffusion of oxygen molecules into the hy- poxic wound tissue, thereby en- hancing multiple molecular and enzymatic functions (32,34).
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TABLE 2 Types of Topical Oxygen Devices
Adapted from ref. 32. Photo sources: Ogenix, https://ogenix.com; EO2, https://www.eo2.com; Natrox, https://www.natroxwoundcare.com; GWR Medical, http://www.topicaloxygen.com, and Advanced Oxygen Therapy, Inc., https://aotinc.net.
New Evidence for TOT
Most of the previous clinical studies on TOT for chronic wounds were observational, in- cluding several comparative co- hort studies. Even when con- ducted prospectively, lack of blinding and effective random- ization brought their generally positive outcomes into question. These concerns have been reme- died with the recent publication of several RCTs and systematic reviews/meta-analyses in chron- ic DFUs that confirm enhanced healing rates in topical oxygen– treated patients compared to good standard care control treatments. Although inconclusive, the first formal, sham-controlled, multi- center RCT using a CDO device on University of Texas (UT) 1A category DFUs was published in 2017 (31). For the primary endpoint of complete healing at 12 weeks in the intention-to- treat (ITT) population (n = 128), 53.8% of active CDO patients healed compared to 49.2% of those receiving the control sham- plus-standard-care treatment (P = 0.42). This trial was general- ly well-designed and conducted and incorporated important fac- ets of high-quality DFU trial de- sign: a run-in period, centralized randomization, double blinding of treatment allocation, and a primary outcome of complete healing at 12 weeks based on ITT populations. Subsequently, the pivotal trial of another CDO device reported pos- itive results in a 12-week multi- center, blinded, sham-controlled, parallel-group clinical trial of UT 1A category DFUs (6). After a 2-week run-in period of standard care treatment with <30% wound area reduction, 146 eligible pa- tients were randomized. The pri- mary outcome again was the per- centage of patients in each group achieving complete healing at 12 weeks. Significantly, 32.4% of CDO-treated patients completely healed compared to 17.7% of those in the sham control group (95% CI 1.05–3.59, P = 0.033). Time to ulcer closure was also shorter in patients who received CDO therapy (P = 0.015).
The most recent multicenter RCT comparing another CDO de- vice against standard care treat- ment for healing chronic DFUs was published in 2021 (33). This 12-week open-label, unblinded study randomized 145 patients with chronic DFUs to either stan- dard care treatment using pri- marily a total contact cast or to the active group receiving TOT plus standard care/cast. Once more, the primary outcome was complete healing at 12 weeks us- ing an ITT analysis. Significantly, 44.4% of those in the TOT group healed at 12 weeks compared with 28.1% of those in the standard care group (P = 0.044). As with other reported TOT studies, there were very few device-related ad- verse events.
Using the cyclically pressur- ized topical wound oxygen device for healing recalcitrant DFUs (UT category 1A–2D), a robust multicenter, sham-controlled, double-blinded RCT was re- ported in 2020 (7). At the first planned (a priori) interim analy- sis point, the active therapy was found to be superior to the sham, with a closure rate at 12 weeks of 41.7% compared to 13.5% (P = 0.007). Enhanced heal- ing rates in the TOT group were also demonstrated by adjusted Cox proportional hazards mod- eling that yielded a hazard ratio of 4.66 (97.8% CI 1.36–15.98, P = 0.004). Distinct from the other RCTs, research- ers in this trial also found that 56% of active-treatment pa- tients achieved 100% healing at 12 months vs. 27% in the sham arm (P = 0.013). Of note, patient adherence to the home-based therapy was very high, and there were no device-related adverse events.
Very recently, this same de- vice was studied to examine its real-world impact on hospital- izations and amputations in pa- tients with DFUs (35). This ret- rospective, comparative cohort study of 202 patients with DFUs found that 6.6 and 12.1% of those using cyclically pressurized top- ical oxygen had hospitalizations and amputations, respectively, at 1 year compared to 54.1 and 41.4%, respectively, of those who had not used this adjunctive topical oxygen modality (each P <0.0001). This represents an 88% reduc- tion in hospitalizations and a 71% reduction in amputations at 1 year compared to patients who did not receive TOT but had access to all other available ad- vanced modalities. Adjusted lo- gistic regression of a matched cohort of these patients demon- strated a nearly ninefold great- er risk of wound-related hospi- talization (odds ratio [OR] 8.667, 95% CI 3.101–24.219, P <0.0001) and a nearly fivefold greater risk of amputation (OR 4.887, 95% CI 1.840–12.985, P = 0.0015) for patients not treated with TOT compared to those who were treated with cyclically pressur- ized topical oxygen.
Three recent systematic re- views with meta-analyses ad- dressed the clinical effectiveness of TOT for healing chronic DFUs (36–38). Despite some method- ological deficiencies and hetero- geneity in populations and study types, they uniformly indicated that TOT (using CDO and cycli- cally pressurized devices) can sig- nificantly improve wound healing among people with chronic DFUs. At the time of writing, a fourth sys- tematic review has been submit- ted for publication with the title “Efficacy of Topical Wound Oxy- gen Therapy in Healing Chronic Diabetic Foot Ulcers: Systematic Review and Meta-Analysis” (MJ Carter, RG Frykberg, A Oropallo, CK Sen, DG Armstrong HKR Nair, TE Serena, unpublished obser- vations). Focused exclusively on recent, high-quality RCTs, this meta-analysis reported an over- all 59% higher probability of heal- ing chronic DFUs at 12 weeks by using adjunctive TOT versus optimal standard care treatment alone (relative risk 1.59, 95% CI 1.02–2.48).
With the growing body of evidence supporting the use of TOT for the treatment of chronic DFUs, an expert multidisci- plinary panel developed a Delphi consensus to establish guidelines for prescribing TOT (39). Engag- ing participants on such topics as published clinical evidence, pre-treatment assessments, indi- cations, duration of therapy, and a focused clinical algorithm, the Delphi approach resulted in the consensus that TOT should be in- corporated into clinical practice as an evidence-based treatment for chronic DFUs.
In summary, TOT has come of age and the evidence supporting its efficacy in healing chronic DFUs can no longer be disputed. Indeed, all four recent systematic reviews corroborate the many ob- servational and controlled studies published in the past two decades that demonstrated the clinical ef- ficacy of TOT. In 2021, an expert consensus panel provided treat- ment guidelines for this therapy and supported its use in clinical practice. Accordingly, it is antici- pated that future evidence-based clinical practice guidelines will similarly recognize the proven benefits of TOT in healing chron- ic DFUs and establish recommen- dations for its use.
TOPICAL THERAPIES FOR NEUROPATHIC DFUs
DFUs are estimated to be prevalent in ~1.7% of people with dia- betes, with an annual incidence of 2.2% (40). In almost all health care economies, the treatment of unhealing wounds consumes a large proportion of total health care resources. Among the rea- sons for this high use of health care resources is the apparent slow healing of DFUs. Data from the National Diabetic Footcare Audit of England and Wales in- dicate that less than half of all the 33,155 DFUs registered between 2015 and 2018 healed by 12 weeks (41), and some never heal.
Despite this, it is surprising how little high-quality evidence we have to support best practic- es in the choice of wound care dressing.
Defining “High-Quality Evidence”
When evaluating the evidence for wound care products, it is import- ant to ensure that all basic aspects of best-practice care were includ- ed in the study. These include sharp debridement when appro- priate, revascularization where needed and possible, treatment of clinical infection, and, most importantly for neuropathic ul- cers, off-loading of the area in line with guidance from the Interna- tional Working Group of the Dia- betic Foot (IWGDF) (42). When best-practice care is not standard- ized in any intervention study of DFUs, it is difficult to be certain that the effects seen in the study are the result of the intervention or simply of differences in the quality of basic care between the compar- ison groups.
RCTs provide the most robust evidence of effect, although as- sessment of the quality of an RCT requires care because of the over- all number of criteria that must be satisfied (43). The concept of “bias” is frequently used in the assessment of intervention tri- als and refers to any factor other than the treatment being studied that could have contributed to the study outcome. Repeated system- atic reviews undertaken on behalf of the IWGDF (44) have conclud- ed that many of the trials of in- terventions to improve healing of DFUs were at high risk of bias.
However, there are a few in- terventions for which the quality of evidence is sufficiently high that we can be relatively cer- tain of their efficacy in improv- ing healing of some DFUs when best-practice care alone has not sufficed. These are described in the sections below.
Topical Sucrose Octasulfate– Impregnated Dressings
In chronic wounds, it is thought that expression of matrix metal- loproteinases (MMPs) can be exaggerated, leading to abnor- mal tissue breakdown and pro- longed healing. A novel dressing has been developed that incorpo- rates sucrose octasulfate into a nonadherent dressing and inhib- its the action of MMPs. The evi- dence to support the clinical effi- cacy of this product comes from one high-quality, multinational, multicenter, double-blinded RCT reporting a statistically signifi- cant benefit from the use of these dressings compared to a place- bo, as described in more detail in the next section (9). The U.K. Na- tional Institute for Care and Clin- ical Excellence has approved the product for use in hard-to-heal neuropathic ulcers even in the ab- sence of apparent ischemia (45). In the United States, this product is not yet available but is undergo- ing clinical studies.
Topical Fibrin and Leucocyte Platelet Patch
One possible treatment option for nonhealing ulcers is the use of platelet-rich plasma or platelet- rich fibrin, which might promote healing of DFUs by promoting the release of cytokines and growth factors involved in tissue repair, angiogenesis, and inflammation. Although the use of platelet prepa- rations is not new, evidence of their benefits has been inconsis- tent. However, the recent development of multilayered patches comprising autologous leucocytes, platelets, and fibrin, which can be made at the bedside without add- ing any reagents, is a new option.
The use of these patches was re- cently assessed in a high-quality, large, multinational, multicenter, outcome-blinded RCT (8). Par- ticipants were patients with hard-to-heal ulcers, defined as those with <50% reduction in ul- cer size after a 4-week run-in pe- riod with good basic care and that were not infected at the time of randomization. Inclusion cri- teria included an ABI of the in- dex limb ³0.7 or palpable foot pulses. Just over half of the par- ticipants (52%) had what could be considered a normal ABI (1.0– 1.4), although no subgroup anal- ysis has been presented regard- ing any possible influence of PAD on the final outcome. Over- all, though, significantly more ul- cers achieved complete healing by 20 weeks in the intervention group than in the group receiving standard care only (45/132 [34%] vs. 29/134 [22%]). A limitation of this study was that it was not pos- sible to blind the patients or those delivering the therapy; however, healing was assessed clinically by an independent assessor blinded to treatment allocation. The in- tervention involved weekly visits for venesection, preparation, and application of the patch, which may have significant cost implica- tions. Nevertheless, the IWGDF guidelines include a cautious rec- ommendation for the use of this intervention (46).
Placenta–Derived Products Human placental membranes contain a combination of growth factors, collagen-rich extracel- lular matrix, and cells, including mesenchymal stem cells, neonatal fibroblasts, and epithelial cells, that provide mechanisms for co- ordinated wound healing. Sever- al products derived from different components of the placenta and umbilical cord have been devel- oped. Cryopreserved preparations contain living cells and growth factors, whereas dehydrated prod- ucts, which are easier to store and handle, contain growth factors but no living cells.
A number of trials have been published (46), and interest in this type of therapy has developed rapidly. Three RCTs of note have been assessed as being at low risk of bias; although none was blind- ed to patients or care providers, all had outcomes assessed in a manner that was blinded with re- gard to allocation group.
The first compared a cryopre- served amniotic membrane al- lograft to good standard care in a single-blinded, multicenter tri- al (47) and found a significant in- crease in the incidence of ulcer closure at 12 weeks (31/50 [62%] vs. 10/47 [21.3%]). This study in- cluded participants with an in- dex ulcer that was ³1 cm2 and not infected at randomization. Both neuropathic and neuroischemic ulcers were included, although the majority were not overtly ischemic; ~22% of the index limbs had an ABI of 0.7–0.9, with the remainder being >0.9. Whether there may have been a difference in outcome dependent on isch- emia is not known.
The second multicenter RCT, which assessed the use of an um- bilical cord product, reported a significant improvement in ulcers healed at 12 weeks compared to good standard care (71/101 [70%] vs. 26/54 [48%]) (48).
The third study, a multicenter RCT of a dehydrated amniotic membrane allograft, also found significant differences in DFU healing at 12 weeks versus good standard care (38/54 [70%] vs. 28/56 [50%]) (49).
The latter two studies included only neuropathic ulcers, as their protocol specified that the per- fusion of the affected limb was “adequate” at randomization, al- though no further details were given. Ulcers were ³1 cm2 and clinically noninfected at random- ization, as in the first study.
Thus, the available evidence suggests that placenta-derived products may have a beneficial effect on neuropathic ulcer heal- ing, although the evidence to date is insufficient to support the su- periority of one product over an- other, and cost-effectiveness in many health care settings re- mains to be established.
In summary, despite the global burden of disease and the high costs to patients and health care economies alike, earlier evidence regarding many topical interven- tions promoted to improve wound healing was poor. The quality of current research is improving, however, and as a result, there are now several interventions that can be recommended with some degree of confidence for use to improve healing of neuropathic or neuroischemic DFUs when usual best-practice care alone has been insufficient to achieve complete wound healing.
THERAPIES FOR
NEUROISCHEMIC DFUs
Recently, there has been an in- creasing realization that ulcer- ation in ischemic feet is a more common form of DFU than ulcer- ation in purely neuropathic feet (50). Ulceration in ischemic feet can be divided into pure ischemic ulcers, which occur in severely or critically ischemic feet, and neu- roischemic ulcers, which devel- op in mild or moderately isch- emic feet. Neuroischemic feet ulcerate in the presence of a less- er degree of ischemia because of coexisting neuropathy. Howev- er, both neuroischemic and isch- emic ulcers are more challenging to heal than nonischemic neuro- pathic ulcers and are associated with a higher rate of amputation and mortality (51).
Until recently, the evidence for the treatment of DFUs was lack- ing and evidence for treating ischemic/neuroischemic DFUs was almost nonexistent because these ulcer types were not in- cluded in clinical trials. Howev- er, the past few years have seen a renaissance in diabetic foot care with the advent of well-designed clinical trials and associated cost-effectiveness analyses (52). Furthermore, moderately isch- emic feet have been included in these trials, together with neu- ropathic nonischemic feet. Additionally, one trial, the Explor- er study, was primarily devoted to the treatment of ulcers in neu- roischemic feet (9).
The Explorer study was a double-blinded RCT investigating the effect of sucrose octasulfate dressing, also known as tech- nology lipido-colloid with nano-oligosaccharide factor (TLC-NOSF) (Figure 1). This dressing is a polyester mesh im- pregnated with a TLC, which is a matrix containing NOSF (sucrose octasulfate potassium salt). In the Explorer study, the sucrose oc- tasulfate dressing was shown to be beneficial in the treatment of noninfected, neuroischemic DFUs that were difficult to heal de- spite best-practice standard care. Neuroischemic feet were defined by the presence of both neuropa- thy and moderate ischemia. This diagnosis was determined by an ABI of £0.9 but a toe pressure ³50 mmHg (or an ankle pressure ³70 mmHg if toe pressure could not be measured). After the trial start- ed, a protocol amendment specified that patients with an ABI >0.9 were also eligible provided they had a TBI £0.7 and toe pressure³ 50 mmHg. This amendment took account of the artifactually high ABI values resulting from medial arterial calcification.
In total, 126 participants were randomized to the sucrose oc- tasulfate dressing and 114 to the control dressing, with both groups having excellent standard care (Figure 1). After 20 weeks of treatment, the proportion of pa- tients whose DFUs healed was significantly greater in the sucrose octasulfate dressing group, at 60 patients (48%) compared to 34 patients (30%) in the control dressing group (95% CI 5–30) yielding an adjusted OR of 2.60 (95% CI 1.43–4.73, P = 0.002).
There was also a significantly shorter healing time of 120 days (95% CI 110–129) as estimat- ed from the Kaplan Meier anal- ysis in participants from the su- crose octasulfate dressing group compared to 180 days (95% CI 163–198, P = 0.029) in the control
D –14 D 0
W 2 W 4
W 8 W 12
W 16
W 20
W 24
W 28
W 32
FIGURE 1 Design of the Explorer study, a double-blinded, stratified RCT conducted in two parallel groups. D, day ; M, month ; NOSF, nano-oligosaccharide factor; W, week. group. Three cost-effectiveness models were derived from the re- sults of the Explorer study with particular regard to the French (53), U.K. (45), and German perspectives (54). The analyses demonstrated that sucrose octa- sulfate is a cost-effective treat- ment compared to a neutral dress- ing and generates cost savings.
In a post hoc analysis that cat- egorized patients according to quartiles of ulcer duration (0–2, 3–5, 6–11, or >11 months), ulcer healing rates decreased as the du- ration of ulceration at baseline in- creased (from 57% in ulcers pre- senting in £2 months to 19% in ulcers presenting at >11 months) (55). Regardless of ulcer duration quartile, higher healing rates were reported in ulcers treated with sucrose octasulfate than in those in the control group. Regarding different locations of DFUs, out- comes were always in favor of the sucrose octasulfate treatment, with healing rates ranging be- tween 43 and 61% within the su- crose octasulfate group compared to 25–40% in the control group.
Delayed healing of neuroischemic DFUs has been related to ex- cess MMPs, which can impair the extracellular matrix and destroy growth factors. The potassium salt of sucrose octasulfate inhib- its MMPs and interacts with and restores the biological functions of growth factors (56). Further- more, it stimulates angiogenesis through the migration and pro- liferation of endothelial cells. Ev- idence that sucrose octasulfate improves perfusion came in a fur- ther study of sucrose octasulfate dressing to treat neuroischemic ulcers (57). Eleven patients with neuroischemic ulcers were in- cluded in a prospective pilot study between July 2019 and March TcPo2 values were assessed at day 0 and monthly until wound healing was achieved. TcPo2val- ues increased significantly be- tween day 0 (29.45 ± 7.38 mmHg) and ulcer healing (46.54 ± 11.45 mmHg, P = 0.016)
Although the Explorer study was devoted to neuroischemic ul- cers, a recent trend in the diabet- ic foot care renaissance has been the inclusion in trials of some ischemic feet together with neu- ropathic feet, but these trials have not been designed to examine outcomes in ischemic feet alone. However, a trial of the multilay- ered patches comprising autol- ogous leucocytes, platelets, and fibrin that was described earli- er in this monograph (8), in ad- dition to reporting overall out- comes, also noted outcomes of ulcers in patients with ischemic feet, as defined by an ABI <1.0. In patients with an ABI of 0.5–0.79, 5/14 (35.7%) healed in the group receiving the multilayered patch compared to 2/16 (12.5%) in the control group. In patients with an ABI of 0.8–0.99, 8/30 (26.7%) healed in the multilayered patch group compared to 6/23 (26.0%) in the control group.
Unhealed DFUs are suscepti- ble to infection and are a prelude to 84% of lower-extremity ampu- tations (58). The aim should be to heal these ulcers as quickly as possible to avoid the catastroph- ic loss of a leg to infection. In dia- betic foot clinics, there has been a paradigm shift away from a focus on ulcers in neuropathic feet and toward ulcers in neuroischemic feet, which occur more frequent- ly. There is now good evidence to support the successful treatment of neuroischemic ulcers with sucrose octasulfate in addition to best-practice standard care (59).
NEGATIVE PRESSURE WOUND THERAPY
NPWT was introduced by Argenta and Morykwas in 1996 and has revolutionized wound care (60,61). It is now the preferred method of treating large and complex wounds in diverse care settings around the globe. “Neg- ative pressure” is a misnomer, as pressure is a positive quanti- ty, but many calculate the differ- ence in pressure applied from atmospheric pressure and re- port it as a negative number. Oth- ers have referred to this form of treatment perhaps more ac- curately as vacuum-assisted clo- sure or sub-atmospheric pressure therapy (62).
Much work has been done on the mechanism of action of NPWT, and it appears that, in both ex- perimental diabetic animals and humans, it increases granulation tissue (62–65) through upregula- tion of the hypoxia-inducible fac- tor 1a (HIF-1a)/VEGF pathway (66). Experimental studies in dia- betic mice have shown a dramat- ic increase in the rate of granu- lation tissue formation and that blood vessels formed when sub- jected to NPWT are more normal and less ectatic than new vessels in wounds treated with an occlu- sive dressing (65–67).
NPWT therapy systems are quite variable (68). A basic sche- matic of an NPWT system is de- picted in Figure 2, including com- ponents that may vary depending on manufacturer and clinical set- ting. It is important to note the de- tails of these components when comparing studies using different NPWT systems.
DFUs are diverse, occurring throughout the foot with depths sometimes going to the bone. Peo- ple who develop DFUs are typically older and have type 2 diabe- tes, often with obesity and several other comorbid conditions (69). To make clinical decisions, clini- cians must rely on the literature, with the highest level of evidence derived from well-designed, pro- spective RCTs (64). However, there have been only a few good RCTs for the treatment of DFUs (70–72).
FIGURE 2 Schematic diagram of NPWT systems with commonly available component options. A wide variety of NPWT systems are available to clinicians today. The interface material is typically an open pore polymeric foam, but some systems use gauze. This material is covered with a semi-occlusive dressing that forms a seal over the wound. Connecting tubing goes to a pump that can apply continuous, intermittent, or periodic vacuum pressure, usually ranging from 50 to 150 mmHg. Wound exudate is collected in a cannister, which frequently is filled with a desiccant or gelation agent. Some systems also have the capacity for wound irrigation.
In designing an RCT, investiga- tors must select a group of patients whose ulcers do not heal com- pletely with conventional treat- ment and include enough patients in each arm of the study to show a difference between the treatment arm and a standard care compar- ison group. Researchers usually exclude patients with severe car- diac, respiratory, or renal diseas- es that would put them at high risk of complications, unrelated to the treatment being studied, during the trial. Once a trial is published, many clinicians extrapolate its results to excluded patient groups, often not realizing that the effica- cy of treatment has not been prov- en in these populations.
In one well-designed RCT, Arm- strong et al. (70) compared NPWT to standard moist wound care in 162 people with diabetes who had partial foot amputations up to the transmetatarsal level. They found a healing rate at 16 weeks of 56% compared to 39% in the standard care group. When Armstrong et al. (71) reanalyzed these data in 2007, they found NPWT to be su- perior in both acute and chronic wounds. In another high-quality RCT, Blume et al., (72) compared NPWT to advanced moist wound therapy in 342 patients with Wag- ner grade 2 or 3 ulcers and found a healing rate at 16 weeks of 43.2 vs. 28.9%.
Although RCTs are the gold standard for medical evidence, many prospective RCTs have still been proven wrong after publication. There are many reasons why this can occur, but one common criticism is that a study includ- ed too few patients, rendering it prone to statistical anomalies.
While most pre-clinical stud- ies of NPWT have shown that it works primarily by increas- ing granulation tissue (62), most RCTs have measured the rate of complete wound closure as a primary endpoint (73). Because many clinicians use NPWT as one of several treatments to heal a wound, complete wound closure may be an imprecise metric to as- sess the effectiveness of NPWT.
Because NPWT has been avail- able for 25 years and is common- ly used in clinical practice, many clinicians feel that conducting a prospective RCT at this late date would be unethical, as it would deny therapy (which they al- ready consider to be effective) to some patients. However, in some areas of the world where NPWT has not yet been established, some recent prospective RCTs have been completed (74).
The use of NPWT in DFUs has been studied with mixed results. In a Cochrane review of NPWT in patients with diabetes, Liu et al. (75) focused on diabetic foot in- fections treated with NPWT com- pared to conventional dressings in eight studies involving 640 partic- ipants and were able to pool data from five of the studies (486 par- ticipants). They concluded that there is low-certainty evidence that NPWT may increase the pro- portion of wounds healed and re- duce the time to healing compared to conventional dressings.
A systematic review and meta- analysis performed by Liu et al. (76) also compared NPWT to conventional dressings. This analysis of data from 11 RCTs involving 1,044 patients found that NPWT was 1.48 times more likely than conventional dress- ings to heal wounds, with a de- creased time to closure (by 8 days) and a reduced risk of ampu- tation (relative risk 0.31).
Three RCTs compared conven- tional NPWT to NPWT with sa- line instillation. Lavery et al. (77) showed no difference in 150 pa- tients, whereas Giri et al. (78) re- ported decreased bacterial burden and decreased wound size in 48 patients. Kim et al. (79) found no differences in their primary end- points but did show a 3.1-fold de- crease in the need for readmission of patients treated with saline in- stillation with NPWT compared to NPWT alone.
In summary, NPWT has resulted in a paradigm shift in the way complex DFUs are treated. There is good evidence to sug- gest that this form of therapy in- creases granulation tissue, and prospective RCTs have shown that it speeds wound healing. The supporting literature has been criticized for comprising low-certainty evidence from trials with risk of bias and imprecision. Additional clinical RCTs com- paring NPWT to standard wound dressings may be difficult to per- form. However, evidence for addi- tional improvement using saline instillation with NPWT is mixed and warrants further study.
Table 3 lists the therapeutic technologies for DFU treatment described above and summarizes their indications, supporting evi- dence, and relative costs.
TABLE 3 Indications, Relative Cost, Supporting Evidence, and Possible Future Directions of Commonly Used Therapeutic Technologies to Treat DFUs
| THERAPEUTIC TECHNOLOGY | COMMON INDICATIONS | RELATIVE COST | LEVEL OF EVIDENCE | PROBLEMS WITH EVIDENCE | POSSIBLE FUTURE DIRECTIONS |
Hyperbaric oxygen therapy
Topical oxygen therapy
Sucrose octasulfate
Autologous leucocyte, platelet, and fibrin multilayered patches
Placenta-derived products
Negative pressure wound therapy
Neuropathic and ischemic ulcers
Neuropathic and neuroischemic ulcers, venous leg ulcers
Nonhealing neuropathic or neuroischemic ulcers
Nonhealing DFUs
Nonhealing DFUs
Large nonischemic DFUs
Several RCTs,
real-world studies, and observational studies, as well
as meta-analyses, showing success
One large, multicenter RCT
One large multicenter RCT
Multiple RCTs
Multiple RCTs and observational studies
Studies have been criticized for bias and large numbers of dropouts or adverse events
Multiple devices, difficult to compare
Only one RCT
Only one RCT
Many of the RCTs have had a small number of patients
Difficulty in blinding
Decline in use of this complex, expensive therapy without robust evidence regarding optimal therapy for specific wounds
Completion of comparative effectiveness studies
Completion of additional comparative clinical trials
Completion of additional comparative clinical trials
Completion of additional comparative clinical trials
Completion of additional RCTs with saline instillation
Looking Ahead: Therapeutic Approaches in the Research and Development Pipeline
CHALLENGES
OF DEVELOPING
THERAPEUTICS FOR DFUs
As an organ, the skin is readily accessible and thus uniquely suit- ed to routine visual assessment and minimally invasive manipu- lation. This is advantageous when the skin incurs injury, permit- ting rapid diagnostic assessment and simple procedural interven- tions such as debridement. More- over, external behavior modifica- tions such as pressure off-loading can more directly modulate skin injury compared to injuries involving other organ systems. Such procedures and modifica- tions can be and are routinely done as best-practice standard care, but an unintended conse- quence is that these opportunities create an additional layer of vari- ance that complicates evaluation of new therapeutics.
For example, a multicenter clinical trial of any biologic dressing or treatment that seeks to assess the rate of wound clo- sure is inherently likely to find variable results, in part because of both the thoroughness of debridement, which varies even for the same physician treat- ing different patients, and vari- able patient compliance with off-loading instructions. Com- pared to trials of cancer thera- pies, in which tumor aggressive- ness can be partially determined through regression based on pre-
and post-treatment metrics, the variance in wound healing stud- ies creates additional “noise” that undermines the ability to statistically power large-scale trials. As a result, clinical trials are either under-powered be- cause traditional power analy- ses are used that do not take this variance into account or aban- doned as unfeasible based on more accurate power analyses that recommend huge treatment groups to obtain meaningful re- sults. Recent examples of failed phase 2 and phase 3 wound heal- ing trials include studies of topi- cal application of repifermin (re- combinant human keratinocyte growth factor-2) for the treat- ment of venous leg ulcers and human platelet-derived growth factor-BB for chronic pressure ulcers. In both cases, investiga- tors were unable to establish sig- nificant changes in the time to complete wound closure, which is the only primary endpoint the
U.S. Food and Drug Administration (FDA) would accept for these trials (80). Thus, although wound healing has been a large focus for the pharmaceutical in- dustry, little real progress has been made in this area.
CONTRARIAN STRATEGIES BASED ON THE CURRENT
REGULATORY LANDSCAPE
Given the inherent challenges as- sociated with wound healing stud- ies, investigators seeking FDA ap- proval for treatments for DFUs have begun seeking alternative ap- proaches in place of the tradition- al clinical trial regulatory pathway. In 2016, the U.S. Congress enact- ed the 21st Century Cures Act to streamline the federal drug ap- proval process (81). A key aspect of this legislation was the explicit engagement by the FDA with both real-world evidence (RWE) and real-world data (RWD) in the drug approval process, including the use of clinical efficacy and safety data from previous trials for the purpose of drug approval for alter- native indications. A consequence of this policy, whether intention- al or not, is an incentive for phar- maceutical companies to first tri- al their nascent drugs against “orphan” conditions (defined as those that affect <200,000 people in the United States), for which drug development is incentivized with tax breaks and prolonged exclusivity rights) to obtain the most fast-tracked approval pos- sible, and then to use data from those trials as RWE to promote ap- proval for the same drugs to treat a broader indication (82). This approach is particularly appeal- ing in the context of DFU heal- ing, given that the broad pathology associated with these lesions can be easily abstracted to orphan indications for multiple skin conditions.
POTENTIAL TARGETS
One example of the orphan drug strategy has been the devel- opment of the small molecule deferoxamine (DFO), an iron che- lator traditionally used to treat hemochromatosis (alternatively referred to as “bronze diabetes”). Diabetic wound healing is associ- ated with significant impairment in new blood vessel growth and el- evated oxidative stress, and DFO has been shown to promote neo- vascularization during tissue re- pair through stabilization of the master hypoxia regulator HIF-1a (83). Investigators at Stanford University recently partnered with the University of Alabama, Birmingham, to trial DFO (delivered through a proprietary hy- drogel patch) for the treatment of an orphan indication ascribed to skin ulcers in patients with sick- le cell anemia (84), which is char- acterized by decreased peripheral oxygenation and impaired heal- ing of skin lesions. In seeking ev- idence to support an orphan drug indication, it is possible to con- duct a smaller, less expensive clin- ical trial and thereby obtain RWE and RWD that can then be used to support approval of DFO drug de- livery devices for the treatment of similar (non-orphan) conditions, including DFUs. These studies will also pave the way for support of similar hypoxia rescue agents such as dimethyloxalylglycine and HIF-1a itself.
In addition to targeting hypoxia and impaired blood vessel growth, strategies for diabetic wound heal- ing have also focused on the aber- rant fibrotic response associated with diabetic skin injury that re- sults in dysfunctional healing. Af- ter tissue repair, wound scars nev- er fully return to their pre-injury state, in part because of hyperpro- liferation of fibroblast cells and their over-secretion of collagen and other extracellular membrane proteins. This hyperfibrotic re- sponse leads to both delayed heal- ing and reduced tissue strength in the resulting scar, increasing the risk of recidivism (85). Strategies aimed at attenuating this problem have focused on the role of mecha- notransduction (i.e., the sensation of mechanical force by resident tissue fibroblasts). Both direct mechanical off-loading and phar- maceutical abrogation of mech- anotransduction signaling have shown early promise as methods to limit the hyperfibrotic response and promote true tissue regenera- tion (86,87).
EVOLUTION OF EVIDENCE- BASED TREATMENT
ALGORITHMS
In addition to new therapeutic products in development, an- other avenue toward increas- ing treatment efficacy for DFUs has been to optimize the appli- cation of existing therapeutic modalities. This effort has been embodied in treatment heuris- tics, wherein providers are giv- en a decision tree from which to determine optimal interven- tions based on observed clini- cal situations. This approach has become increasingly popular in large health care systems such as Kaiser Permanente and Banner Health, as well as large, nation- al wound center networks such as Healogics (88). The motiva- tion for this strategy is that ag- gregate RWE collected through nationwide data-mining efforts can be superior to the clinical ex- periences of individual provid- ers in shaping decision-making. Such approaches are appealing, but often are not grounded in or validated through publicly avail- able study data, and the ADA has yet to endorse a single wound healing heuristic. It is likely that nationwide consortiums would be required to gather the RWD needed to develop a comprehen- sive treatment algorithm. Re- cently, the National Institutes of Health has pioneered a Diabetic Foot Consortium to sponsor col- laboration among academic hos- pitals (89). Early trials are still in development, but this initia- tive reflects the promise of col- laborative research to gather the necessary wound healing data across time and space to power the RWD needed to inform deci- sion guidance.
BIG DATA DECISION SUPPORT TO FLAG HIGH-RISK WOUNDS
Since the passage in the United
States of the Affordable Care Act and the resulting widescale im- plementation of electronic health record systems, it has become in- creasingly clear that tradition- al approaches to the analysis of RWD such as logistic regres- sion and multivariate mixed ef- fects modeling are insufficient to handle the rapidly expand- ing number of measured clini- cal variables. More sophisticat- ed machine learning techniques such as neural networks, support vector machines, and deep learn- ing approaches have already been adopted in electrocardiogram as- sessment and radiographic image detection, in which data are less modular. Unlike traditional stud- ies that compare outcomes of in- terest against pre-determined pa- rameters expected to influence those outcomes, artificial intel- ligence–based approaches are capable of taking unbiased sur- veys of all available data param- eters with the goal of classifying one or more outcome sets. This approach has proven success- ful most notably in the field of diagnostic radiology, in which automated lesion detection now serves as a standard-of-care tool for decision support at most large medical centers.
Similar efforts applied to wound
classification have yet to gain trac- tion, in part because of the chal- lenges of incorporating direct wound assessment (90). Howev- er, as image processing becomes faster and less expensive, decision support based on raw wound pho- tos should become more achiev- able. Furthermore, the increased adoption of wearable, so-called “smart” devices in the United States, discussed in more de- tail below, is likely to provide vast quantities of new data to assess outcomes using time course mea- surements. Early efforts are al- ready underway to translate wear- able wound bandages into systems for the early detection of problem- atic wounds, with the prospect of direct therapeutic intervention similar to that achieved with au- tomated insulin pumps. Such per- sonalized treatment strategies may exemplify the next genera- tion of diabetic wound care in the coming decades.
Keeping the Ulcer Healed: Patients’ Views on Digital Technology in the Prevention of Ulcer Recurrence
Despite substantial advances in DFU management, ulcer recur- rence rates remain high, ranging from 40% within 1 year to 65% within 5 years (91). The reasons for DFU recurrence are believed to be both biological and behavioral (92). Because people at high DFU risk have no symptoms to prompt them to check their feet, psycho- educational interventions have traditionally focused on behavior- al modifications designed to serve as substitute self-care cues in the absence of foot sensation and minimize the impact of neuro- pathic risk factors. These behav- ioral changes include the adop- tion of preventive foot self-care actions (e.g., daily foot checks) and avoidance of behaviors that, although appropriate for people with intact sensation in their feet, can potentially damage the feet of people affected by neuropathy (e.g., walking barefoot). Among the commonly examined psy- chological determinants of foot self-care are patients’ cognitive and emotional representations of DFU risk (93–95), depression (96–98), and cognitive function (99), with the strongest evidence to date supporting a link between patients’ interpretation of their DFU risk, associated emotion- al responses, and preventive foot self-care (100).
However, mounting evidence indicates that commonly advocat- ed behavioral advice may not be effective enough to prevent DFU recurrence (98,101,102). Several reports have shown that depres- sion and nonadherence to foot self-care predict first but not re- current DFUs (96,98), findings that were recently supported by a systematic review (103). The ob- servation that basic foot self-care behavioral strategies are ineffec- tive for secondary DFU preven- tion was also supported by sev- eral trials demonstrating that, although participants in enhanced foot care education groups report- ed improved foot self-care, no sig- nificant differences in DFU re- currence were observed between the control and the intervention groups (101), as participants had biological DFU risk factors that are beyond control by such inter- ventions (102).
To augment current preventive foot self-care behaviors, wear- able technologies are being de- veloped that can continuously monitor DFU risk factors and pro- vide real-time alerts to people at high DFU risk, thereby prompting them to undertake protective ac- tion (104). Digitally connected, or “smart,” flexible sensors implanted in insoles or socks connect with mobile apps to allow mon- itoring and remote visualize of in-shoe plantar pressure and tem- perature. This strategy not only represents a paradigm shift in DFU risk screening and monitor- ing, but also, crucially, transforms foot-care education. The adage that “a picture is worth 1,000 words” is particularly relevant to this patient population, for whom symptoms and signs cannot be re- lied on when conveying messages about DFU risk. As a result, people often have poor comprehension of the potential for serious com- plications, especially with regard to their intrinsic DFU risk from factors such as foot deformities or elevated foot pressures, which, in turn, leads to a lack of effective foot self-care (93). By allowing people to visualize their personal DFU risk, digital technologies are likely to enhance patients’ active involvement in DFU prevention.
Although promising, digital technologies create additional layers of complexity to preven- tive foot self-care for people at high DFU risk. These complexi- ties include differing levels of fa- miliarity with and dependence on technology and conditions of functionality such as other coex- isting diabetes complications and reduced mobility, as well as vari- able need for support from health care providers and family mem- bers (105). Yet, there is a dearth of research examining determinants of patient acceptance of digital technology in DFU prevention. Several systematic reviews that evaluated telemedicine in diabet- ic foot disease either focused on the effectiveness of the devices or evaluated users’ experience in the management of active DFUs rath- er than prevention (106–108).
A recent systematic review (109) of patient and provider perspectives on smart wearable technology in DFU prevention identified only five publications (110–114) of low to moderate methodological quality. Two studies used a quantitative/ questionnaire study design and focused on the patient perspec- tive (110,111), whereas three studies included a mixed, ques- tionnaire/interview design and explored patient and/or podia- trist perspectives (112–114). Four studies focused on a smart insole system to measure plantar foot pressures (110,112–114), whereas one included a smart sock device for monitoring plantar foot tem- peratures (111). Only one group of researchers, using the Unified Theory of Acceptance and Use of Technology (UTAUT)-based questionnaire (115), explicitly addressed the psychological fac- tors influencing patient and po- diatrist behavioral intention to adopt a smart insole device (112– 114). These researchers identi- fied important differences be- tween patients and podiatrists with regard to factors determin- ing their behavioral intention to adopt a smart insole. Although positive attitudes to digital tech- nology and the belief that one could develop the skills to adopt a smart insole (self-efficacy) were key in activating patients (112), performance expectancy or the belief that a smart insole is effective in mitigating DFU risk was the single most important factor motivating podiatrists to use smart insoles in their clinical practice (113). Qualitative anal- yses revealed that participating podiatrists believed that the in- sole would increase patient en- gagement and self-efficacy. However, concerns were raised about cost, footwear issues, and the de- vice’s utility for elderly and re- mote populations.
The same research group re- cently evaluated the feasibility of podiatrist-led health coaching to facilitate adoption of a smart shoe insole in people at high DFU risk (114). The 4-week intervention assessed participants’ intention to adopt smart insoles and actual insole usage. Using health coach- ing techniques, podiatrists suc- cessfully facilitated the adoption of a smart insole by study par- ticipants, as evidenced by insole wear time that exceeded that re- ported in previous studies using a similar device but without health coaching (110). However, there was a significant decline over time in responses to alert-based cues for foot pressure off-loading. This finding contrasts with a study by Najafi et al. (110) show- ing that individuals who received more alert-based cues for plantar pressure off-loading had reported better adherence than those in a group receiving fewer alerts.
It is possible that there is an upper threshold at which alerts would lead to declining adher- ence. Because the participants in the health coaching intervention (114) received, on average, twice as many alerts per hour than those participating in a study by Naja- fi et al. (110), they may have de- veloped response fatigue, con- tributing to a lower percentage of successful responses. Fur- thermore, scores on the UTAUT- based questionnaire demonstrat- ed significant post-trial reduc- tions in attitude toward and be- havioral intention to use the smart insole (114). Qualitative findings from this study demonstrated that behavioral intention to use digital technology may change as a func- tion of a person’s experience with the device. Study participants re- ported frustration when the de- vice malfunctioned and felt that repeated alerts were becoming intrusive during daily activities. For participants who had not pre- viously experienced a DFU, the feedback appeared random and significantly diminished their lev- el of trust in the device. On the other hand, those with a previous DFU, although they believed the device provided accurate feed- back, felt that there was little they could do to constantly mitigate high pressure areas on the bot- toms of their feet. These obser- vations resonate with earlier re- ports highlighting the importance of DFU experience in shaping pa- tients’ views about their DFU risk and foot self-care (93). Moreover, unsatisfactory patient experienc- es with the smart insole negatively affected podiatrists’ intentions to adopt the device in practice (114). However, both, patients and podi- atrists still saw value in real-time foot monitoring and indicated that refinement of the device would increase the likelihood of future adoption. Thus, the results of the focus group discussions clarified, at least to some extent, the some- what unexpected trend toward a significant reduction in perceived usefulness of the device: it did not meet participants’ initial expecta- tions. There is, therefore, a need for early patient and provider involvement in the development and evaluation of digital technolo- gy devices if we are to initiate and sustain the desired foot self-care behavior change.
Additionally, findings from these reports highlight an import- ant limitation of using behavioral intention as a proxy for technology acceptance: behavioral inten- tion provides little insight into actual technology use. Further- more, theoretical models such as the UTAUT are typically so- cial cognition models and thus do not incorporate illness-specific domains such as patient percep- tions of their DFU risk and spe- cific emotional responses that were previously identified as im- portant predictors of preventive foot self-care (93). It is therefore unlikely that people will adopt digital technology if they do not appreciate their DFU risk. Furthermore, digital technology adoption is a dynamic and inter- active process. This fact necessi- tates that technology implemen- tation be evaluated longitudinally so that emerging issues between people at high DFU risk and health care delivery can be iden- tified and addressed. Nonetheless, even in its infancy, this rapidly evolving area of research provides valuable insights into patient and provider views of digital technol- ogy. Evaluation should continue into interventions to improve pa- tients’ acceptance and sustained use of digital technology and to reduce DFU recurrence.
in high-risk populations, for both monitoring and extending the number of ulcer-free days in re- mission (120–123).
Additionally, external pressure for intensive assessment of in- novation has coincided with the refinement of existing technolo- gies such as NPWT, as well as the development of novel technol- ogies such as autologous leuko- cyte dressings and sodium octa- sulfate, which are now supported by data from well-designed RCTs (8,9). Furthermore, therapies that previously were considered less mainstream, such as TOT, have recently gained in popularity as a result of a more robust clini- cal evidence base from multiple RCTs and meta-analyses (37,38).
Finally, and perhaps most importantly, we are making strides in our understanding of the dia- betic foot in remission. Our as- sessment of any new therapies should not only consider reduc- tion in the time to ulcer healing, but also the impact of the thera- py in reducing ulcer recurrence rates, which are, of course, rep- resented by hospitalization and amputation rates post-healing. In this regard, the recent real-world publication of TOT experience single DFU recurrence (91,125). The concept of remote patient monitoring, once an exotic idea, is now incorporated more rou- tinely (126,127). Efforts to use thermometry and other tools in the way we have collectively used glucometry are emerging. In oth- er words, dosing activity by check- ing for inflammation of the foot, just as we might dose insulin by checking glucose levels, may soon become commonplace (128).
This ADA Clinical Compendium is the third in a series focus- ing on foot care for people with di- abetes (1,2). Although published in the midst of a global pandem- ic, it is paradoxically the most op- timistic installment yet. Focusing not just on treating and prevent- ing communicable disease, but also on improving our approach- es to noncommunicable diseases may be our collective therapeu- tic North Star. Mitigating acute and chronic disease that starts at the end of the body—the hum- ble foot—is a worthwhile endeav- or that may yield substantive rewards that will benefit our pa- tients and society long after the pandemic subsides.
ACKNOWLEDGMENTS
Editorial and project management in two U.S. Department of Vet-
services were provided by Debbie
Conclusions
Complications of the diabetic foot remain common, complex, and costly. This situation has been ex- acerbated by reduced access to care during the COVID-19 pan- demic (116–119). However, as with any existential tragedy, pos- itive pressure toward innova- tion can emerge. In this case, we are enjoying an unprecedented surge in pragmatic outreach to and the use of digital technology
erans Affairs hospitals (35) re- ported reductions of 88 and 71% in hospitalizations and amputa- tions, respectively, at 12 months in patients receiving TOT com- pared to those in the standard care group. With the understand- ing that ~40% of DFUs will re- cur on the same or contralater- al limb by 1 year (rising to ~66% by 3.75–5 years) (124), maximiz- ing ulcer-free, hospital-free, and activity-rich days for our patients becomes a more noble (and real- istic) goal than preventing every
Kendall of Kendall Editorial in Richmond, VA.
FUNDING
This publication was supported by an unrestricted educational grant from AOTI.
AUTHOR CONTRIBUTIONS
A.J.M.B. and D.G.A. served as
co-editors and, as such, co-wrote the introduction and conclusion and reviewed and edited the entire manuscript. M.L. wrote “History of Oxygen Therapy for the Treatment of DFUs.” R.G.F. wrote “Topical Oxygen Therapy.” F.L.G. wrote “Topical Therapies for Neuropathic DFUs.” M.E.E. wrote “Therapies for Neuroischemic DFUs.” D.P.O. and K.K. wrote “Negative Pressure Wound Therapy.” G.C.G. and M.J.
wrote “Looking Ahead: Therapeutic Approaches in the Research and Development Pipeline.” L.V. wrote “Keeping the Ulcer Healed: Patients’ Views on Digital Technology in the Prevention of Ulcer Recurrence.”
A.J.M.B. and D.G.A. are the guarantors of this work.
DUALITIES OF INTEREST
M.L. has received research funding from Reapplix. R.G.F. has received research funding from and is a consultant to Advanced Oxygen Therapies, Inc. F.L.G.’s employer received funding for her research time to conduct the LeucoPatch trial, which was funded by Reapplix. She has also received honoraria to speak at educational meetings sponsored by Urgo Medical and MiMedx. M.E.E. has received honoraria from Urgo Medical for consultancy, advisory board attendance, and lectures.
D.P.O. has received research funding from KCI through a sponsored grant to Brigham and Women’s Hospital.
G.C.G. is the founder of and has equity in Theris Medical. No other potential conflicts of interest relevant to this publication were reported.
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technology in diabetic foot ulcer prevention: a systematic review. Medicina (Kaunas) 2021;57:1359
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temperature-monitoring socks for home use in patients with diabetes: observational study. J Med Internet Res 2018;20:e12460
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with diabetes-related peripheral neuropathy. Sensors (Basel) 2021;21:3984
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the-surge-delayed-chronic-wound- care-during-covid-19. Accessed 22
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amputation and death in people with diabetes. J Am Podiatr Med Assoc. Online ahead of print on 25 March 2020 (doi:10.7547/20-051)
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foot in remission. J Wound Care 2018;27(Suppl. 4):S3–S4
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Suggested citation:
Boulton AJM, Armstrong DG, Löndahl M, Frykberg RG, Game FL, Edmonds ME, Orgill DP, Kramer K, Gurtner GC, Januszyk M, Vileikyte L. New Evidence-Based Therapies for Complex Diabetic Foot Wounds. Arlington, Va., American Diabetes Association, 2022 (https://doi.org/10.2337/db2022-02)