SerenaGroup Research Institute

Background: Diabetic foot ulcers (DFUs) are chronic wounds associated with high morbidity, mortality, and economic burden. Current standard of care (SOC) achieves less than optimal healing rates, highlighting the need for novel and cost-effective therapies. Methods: An interim analysis of this multicenter, prospective, randomized controlled modified platform clinical trial evaluated the efficacy of multiple cellular, acellular, and matrix-like prod-ucts (CAMPs) with SOC versus SOC alone. The primary endpoint was percentage of target ulcers achieving complete wound closure in 12 weeks, defined as 100% reepithelialization without drainage for two consecutive weeks, confirmed by blinded independent review. Results: In Intent-To-Treat (ITT), the dual layer amnion/chorion membrane allograft (DLACG) with SOC arm achieved a 58.3% closure rate versus 13.3% with SOC alone, a 45% absolute gain that was statistically significant (n=12, 95% CI 15.7% to 68.4%, p=0.001, α=0.05). All other treatment groups were not significant in the ITT population. In Per Protocol (PP), analysis of the four-layer amniotic membrane allograft (FLAG) with SOC arm achieved a 63.6% closure rate versus 23.8% with SOC alone, a 39.8% absolute gain that was statistically significant (n=11, 95% CI 4.5% to 64.8%, p=0.027, α=0.05). All other treatment arms were not significant in PP population. Additionally, the percent area reduction (PAR) from TV-1 to TV-13 measured weekly with digital photographic planimetry, using an imaging device, and physical examination were analyzed. For ITT and PP populations, all treatment arms outperformed SOC on average and median wound-area reduction. For PP, demographic summary statistics were analyzed to de-termine randomized baseline balance across groups, which was achieved with no statistically significant differences between groups at the time of interim analysis. Conclusion: The interim analysis revealed that the placental membranes products trended to-ward superiority over SOC. The statistical significance in the ITT population for DLACG suggests that this product is superior to SOC.

A common complication of diabetes, diabetic foot infections, can lead to devastating complications. Early antibiotic and surgical treatment are key to preserving the affected limb. Emergent surgical intervention is the mainstay of therapy; however, despite aggressive surgical debridement, some patients still go onto lower extremity amputation. Amputation in diabetics has a prognosis worse than the most common cancers. The need for advanced therapies in the treatment of the infected diabetic foot remains an unmet need. This case series reviewed the use of a novel Topical Desiccating Agent (TDA), containing methanesulfonic acid, in combination with surgical debridement and antibiotics in the treatment of severe diabetic foot infections. Research suggests that the addition of a TDA facilitates debridement and disrupts both planktonic and biofilm-based bacteria promoting healing and decreasing the time to definitive reconstruction. A total of eleven patients were treated with the novel TDA. It was applied in the operating room at the time of the initial surgical intervention. Two cases are presented in detail. Overall, there appeared to be a more complete debridement and more rapid time to grafting with the addition of the desiccant. Further research into the role of TDAs in the treatment of the infected diabetic foot is warranted.

High bacterial burden is one of several reasons that wounds fail to heal. At present, clinicians rely primarily on clinical signs and symptoms (CSS) to diagnose infection in hard-to-heal wounds; however, studies have demonstrated that CSS can be unreliable. This is especially true in the early stages of bacterial infection. Bacteria release proteases, virulence factors that promote invasive infection. This clinical trial evaluated the use of bacterial protease activity (BPA) as a biomarker to detect whether a wound was in the period of pathogenicity, prior to overt clinical signs. Participants were drawn from six US wound centres and had their wounds assessed clinically for infection. In addition, wound fluid swabs were collected and analysed for BPA, inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)), and cultured for quantitative microbiology. A total of 366 patients were recruited. The median BPA level increased with the increasing number of signs of infection. The majority of wounds tested positive for elevated BPA prior to exhibiting at least three CSS of infection, the level at which the criteria for infection are met. BPA tended to increase with the bioburden (colony forming unit (CFU)/ml) although some wounds with high bioburden were negative for BPA, and others with low bioburden were positive for BPA. The mean levels of IL-1β and TNF-α were significantly higher in BPA-positive wounds (p<0.0001 and p=0.0002, respectively). The results of this clinical trial suggest that measuring BPA can lead to the early detection of pathogenic bacteria in the wound that impede wound healing and may progress to invasive infection. In a large percentage of cases, BPA detected virulent bacteria in the absence of CSS of infection. As a biomarker, BPA has an advantage over measuring bacterial load-hard-to-heal wounds are often colonised with non-pathogenic bacteria that do not inhibit wound healing and, conversely, a low number of highly virulent species could disrupt the healing process.

A growing body of evidence supports the use of topical oxygen therapy (TOT) in the treatment of diabetic foot ulcers (DFUs). In addition, anecdotal evidence suggests that topical oxygen may be effective in the treatment of other wound types. In May 2021, experts in the field of wound healing from across the US assembled in New Orleans for the inaugural Leaders in Wound Healing conference. In an interactive session dedicated to TOT, several physicians presented and debated the evidence for TOT. Experts in the audience also shared their experiences in treating patients with TOT. The consensus of the experts recommended the use of TOT in DFUs and supported payer reimbursement for the modality. However, they stressed the need for a guidance document on the use of TOT in patients with hard-to-heal wounds. Following the conference, a Delphi method was employed to establish consensus guidelines for prescribing TOT. A multidisciplinary panel of 24 wound experts (15 wound specialists, six vascular surgeons, one plastic surgeon, one critical care provider and one PhD researcher) participated in two rounds of questionnaires. The Delphi survey questions focused on the indications for topical oxygen, when to prescribe the therapy, pretreatment work-up, visit frequency and length of therapy. A clinical workflow algorithm was also included as part of the Delphi. After two rounds, the Delphi participants were able to reach consensus of >77% on when to prescribe topical oxygen, the wound types that may benefit from the therapy, pretreatment wound preparation and work-up and length of therapy. The goal of the guidelines is to standardise the use of topical oxygen and inform further research efforts.

Detection of bacterial burden within or near surgical wounds is critical to reducing the occurrence of surgical site infection (SSI). A distinct lack of reliable methods to identify postoperative bioburden has forced reliance on clinical signs and symptoms of infection (CSS). As a result, infection management has been reactive, rather than proactive. Fluorescence imaging of bacterial burden (FL) is positioned to potentially flip that paradigm. This post hoc analysis evaluated 58 imaged and biopsied surgical site wounds from the multi‐centre fluorescence imaging assessment and guidance clinical trial. Diagnostic accuracy measures of CSS and FL were evaluated. A reader study investigated the impact of advanced image interpretation experience on imaging sensitivity. Forty‐four of fifty‐eight surgical site wounds (75.8%) had bacterial loads >104 CFU/g (median = 3.11 × 105 CFU/g); however, only 3 of 44 were CSS positive (sensitivity of 6.8%). FL improved sensitivity of bacterial detection by 5.7‐fold compared with CSS alone (P = .0005). Sensitivity improved by 11.3‐fold over CSS among clinicians highly experienced with FL interpretation (P < .0001). Surgical sites that reach the stage of referral to a wound specialist frequently harbour asymptomatic high bacterial loads that delay healing and increase infection risk. Advanced imaging of pathological bacterial burden improves surgical site monitoring and may reduce the rate of SSIs.

Aim: Compare foam dressings- Mepilex Border Flex (MxBF), Allevyn Life (AL) and Optifoam Gentle EX (OGEX) -in treatment of chronic wounds. Materials & methods: Prospective, randomized, controlled trial (crossover design). Subjects received one dressing for 2weeks, then comparator dressing for following 2weeks. Wound/periwound characteristics evaluated weekly at dressing change. Primary endpoint: dressing durability (incidence of exudate strikethrough). Results: Higher incidence of intact dressings (no strikethrough) at Day 7 (Week1) with MxBF (6/17; 35.3%) compared with AL (1/18; 5.6%), and with MxBF (7/16; 43.8%) compared withOGEX (2/16; 12.5%;p<0.05). No significant differences between groups regarding wound size reduction. Conclusion: MxBF had statistically greater durability than AL/OGEX during first critical week of treatment.

Objective: High bacterial load contributes to chronicity of wounds and is diagnosed based on assessment of clinical signs and symptoms (CSS) of infection, but these characteristics are poor predictors of bacterial burden. Point-of-care fluorescence imaging (FL) MolecuLight i:X can improve identification of wounds with high bacterial burden (>104 colony-forming unit [CFU]/g). FL detects bacteria, whether planktonic or in biofilm, but does not distinguish between the two. In this study, diagnostic accuracy of FL was compared to CSS during routine wound assessment. Postassessment, clinicians were surveyed to assess impact of FL on treatment plan.Approach: A prospective multicenter controlled study was conducted by 20 study clinicians from 14 outpatient advanced wound care centers across the United States. Wounds underwent assessment for CSS followed by FL. Biopsies were collected to confirm total bacterial load. Three hundred fifty patients completed the study (138 diabetic foot ulcers, 106 venous leg ulcers, 60 surgical sites, 22 pressure ulcers, and 24 others).Results: Around 287/350 wounds (82%) had bacterial loads >104 CFU/g, and CSS missed detection of 85% of these wounds. FL significantly increased detection of bacteria (>104 CFU/g) by fourfold, and this was consistent across wound types (p < 0.001). Specificity of CSS+FL remained comparably high to CSS (p = 1.0). FL information modified treatment plans (69% of wounds), influenced wound bed preparation (85%), and improved overall patient care (90%) as reported by study clinicians.Innovation: This novel noncontact, handheld FL device provides immediate, objective information on presence, location, and load of bacteria at point of care.Conclusion: Use of FL facilitates adherence to clinical guidelines recommending prompt detection and removal of bacterial burden to reduce wound infection and facilitate healing.

The current public health crisis has highlighted the need to accelerate healthcare innovation. Despite unwavering levels of cooperation among academia, industry, and policy makers, it can still take years to bring a life-saving product to market. There are some obvious limitations, including lack of blinding or masking and small sample size, which render the results less applicable to the real world. Traditional randomized controlled trials (RCTs) are lengthy, expensive, and have a low success rate. There is a growing acknowledgement that the current process no longer fully meets the growing healthcare needs. Advances in technology coupled with proliferation of telehealth modalities, sensors, wearable and connected devices have paved the way for a new paradigm. Virtual randomized controlled trials (vRCTs) have the potential to drastically shorten the clinical trial cycle while maximizing patient-centricity, compliance, and recruitment. This new approach can inform clinical trials in real time and with a holistic view of a patient’s health. This paper provides an overview of virtual clinical trials, addressing critical issues, including regulatory compliance, data security, privacy, and ownership.

Infection in chronic wounds proceeds along a continuum from contamination to colonization and eventually to systemic infection. All open wounds are contaminated with bacteria; however, in this state, the bacteria are harmless: they do not compete with host cells for oxygen and nutrients or injure the tissue. Over time, bacteria will colonize a chronic wound. The colonizing bacteria replicate in the wound bed. They may compete with host cells for nutrients, which in turn impedes wound healing, but they do not invade host tissues. At a subsequent stage, the bacteria begin to produce proteases (virulence factors) that break down host tissue, allowing the bacteria to invade deeper into the wound bed. Unchecked local and eventually systemic infection will ensue. In the past, the term “critical colonization” loosely described the transition from colonization to infection. However, this is a misnomer. Once the bacteria in the wound progress from a colonized state to invasive microorganisms, the term “colonization” is no longer appropriate. At this stage, the bacteria actively produce virulence factors that degrade host tissue, delay wound healing, and increase the risk for systemic infection. A recently completed multicenter randomized clinical trial1 conducted at seven centers in the US evaluated a diagnostic designed point-of-care test to detect the presence of bacterial protease activity (BPA) in chronic wounds. The trial demonstrated that in 39% of chronic wounds BPA increases prior to any signs or symptoms of infection. Therefore, I suggest the term point of pathogenicity to describe this stage of the continuum, rather than critical colonization. It is the point at which bacteria begin producing proteases that break down host tissues leading to infection. In the absence of treatment, ulcers reaching the point of pathogenicity will proceed to active infection. The clinical signs and symptoms of infection in chronic wounds lag behind the production of harmful proteases or may never materialize despite active infection. In previous clinical trials, 25% of wounds had active infection in the absence of clinical signs and symptoms.1–3 The signs and symptoms of infection may not appear until the patient is suffering from systemic limb and life-threatening infection. In the aforementioned large study (266 patients),1 6 patients had ulcers with elevated BPA prior to the development of observable clinical signs or symptoms of infection. This group developed sepsis and underwent amputation of the affected extremity. The data strongly suggest that the early discovery of elevated BPA, at the point of pathogenicity, would have led to earlier intervention and perhaps obviated the need for amputation. In conclusion, the evidence suggests that there is a point at which bacteria transition from colonization to active invasion. This is heralded by the production of bacterial proteases that do not immediately lead to clinical signs and symptoms of infection in chronic wounds. I suggest the term point of pathogenicity for this phase in the infection continuum. Failure to recognize and treat patients at this stage can have serious consequences, such as amputation and sepsis. The advent of testing for BPA in chronic wounds may result in early detection of infection at the point of pathogenicity and decrease the incidence of infectious complications. Thomas E. Serena, MD SerenaGroup, Cambridge, Massachusetts

Amnion and chorion allografts have shown great promise in healing diabetic foot ulcers (DFUs). Results from an interim analysis of 40 patients have demonstrated the accelerated healing ability of a novel aseptically processed, dehydrated human amnion and chorion allograft (dHACA). The goal of this study was to report on the full trial results of 80 patients where dHACA was compared with standard of care (SOC) in achieving wound closure in non‐healing DFUs. After a 2‐week screening period, during which patients with DFUs were unsuccessfully treated with SOC, patients were randomised to either SOC alone or SOC with dHACA applied weekly for up to 12 weeks. At 12 weeks, 85% (34/40) of the dHACA‐treated DFUs healed, compared with 33% (13/40) treated with SOC alone. Mean time to heal within 12 weeks was significantly faster for the dHACA‐ treated group compared with SOC, 37 days vs 67 days in the SOC group (P = .000006). Mean number of grafts used per healed wound during the same time period was 4.0, and mean cost of the tissue to heal a DFU was $1771. The authors concluded that aseptically processed dHACA heals DFUs significantly faster than SOC at 12 weeks.