Recombinant human platelet-derived growth factor BB (rhPDGF-BB), is the only growth factor approved by the US Food and Drug Administration (FDA) for tissue regeneration and rejuvenation indications. It has received four FDA approvals for both soft tissue (e.g., skin) and hard tissue regeneration/rejuvenation. Regranex gel, 0.01% rhPDGF-BB, is the only growth factor approved by the FDA for the promotion of skin wound healing. While the safety of one and two 15 g tubes of Regranex, generally sufficient for up to 60 daily applications onto open skin wounds, has never been questioned, a decade after its introduction in 1997, a boxed warning regarding rates of cancer mortality was placed on its label for daily use of three or more tubes. This was based on a mathematical calculation on incomplete data from an insurance claims database which was subsequently invalidated with the addition of three more years of data. Removal of this warning from the label required another decade and several very large propensity-matched database studies including over 13,000 patients. These studies provided incontrovertible proof that up to 140 daily applications (≥ 4 tubes) of rhPDGF-BB onto open skin wounds are safe, with no increased risk of either cancer development or cancer mortality. Removing a boxed warning is an arduous task that requires extensive and robust evidence; less than 4% of box warnings are removed once placed. Thus, the successful removal of the boxed warning from the Regranex label should reassure both prescribers and patients of the product's safety.

Objective: SN514 is a thermolysin-like enzyme under development as a debrider. Preclinical and non-clinical studies supported a first in human healthy volunteer study to predict the need for protection of periwound skin.Approach: Pharmacologic activity testing compared in vitro digestion of collagen, fibrin, and elastin with relevant enzymes. A Yorkshire pig model of burn injury was used to evaluate debridement over 10 days and effects on intact skin. A human 21-day cumulative irritation study using Webril patches taped to the backs of 38 healthy adult volunteers compared four enzyme concentrations (0.10%, 0.20%, 0.40%, and 0.80% w/w) with the hydrogel vehicle, saline (low irritant control), and 0.2% sodium lauryl sulfate (positive irritant control) using randomized placements and blinded evaluation.Results: SN514 showed excellent digestion of fibrin, elastin, and collagen in vitro. Burn wound studies in Yorkshire pigs showed efficient eschar debridement with minimal periwound erythema. Direct treatment on intact porcine skin for 5 days produced no to limited erythema. The preclinical findings of minimal irritation with SN514 were verified by a Phase 1 first-in-human 21-day cumulative skin irritation test. Irritation was observed to increase stepwise by concentration, confirming formulation accuracy. Each enzyme concentration was found to be "possibly mild in use" (Berger and Bowman method). No treatment emergent adverse events were observed during the study.Innovation: A fast-acting enzyme with a favorable irritation profile, prepared as a stable, ready to use hydrogel formulation, overcomes many recognized shortcomings of enzyme debriders.Conclusion: The overall findings support clinical dose range testing for tolerance and preliminary efficacy.

An open label, multicenter 16-week trial of cryopreserved human umbilical cord (TTAX01) was previously undertaken in 32 subjects presenting with a Wagner grade 3 or 4 diabetic foot ulcer, with 16 (50%) of these having confirmed closure following a median of one product application (previous study). All but two subjects (30/32; 94%) consented to participate in this follow-up study to 1-year postexposure. No restrictions were placed on treatments for open wounds. At 8-week intervals, subjects were evaluated for adverse events (AEs) and wound status (open or closed). Average time from initial exposure to end of follow-up was 378 days (range 343-433), with 29 of 30 (97%) subjects completing a full year. AEs were all typical for the population under study, and none were attributed to prior exposure to TTAX01. One previously healed wound re-opened, one previously unconfirmed closed wound remained healed, and nine new wound closures occurred, giving 25 of 29 (86.2%) healed in the ITT population. Three of the new closures followed the use of various tissue-based products. Three subjects whose wounds were healed required subsequent minor amputations due to osteomyelitis, one of which progressed to a major amputation (1/29; 3.4%). One additional subject underwent two minor amputations prior to healing. Overall, the study found TTAX01 to be safe in long-term follow-up and associated with both a low rate of major amputation and a higher than expected rates of healing.

Clinical trials of potential new therapies for diabetic foot ulcers rarely enroll patients whose wounds extend to muscle, fascia, or bone with clinical and radiographic evidence of underlying osteomyelitis. An open‐label, multicenter trial of cryopreserved human umbilical cord (TTAX01) was undertaken in 32 subjects presenting with such complex wounds with a mean duration of 6.1 ± 9.0 (range: 0.2–47.1) months and wound area at screening of 3.8 ± 2.9 (range: 1.0–9.6) cm2. Aggressive surgical debridement at baseline resulted in 17 minor amputations and an increase in mean wound area to 7.4 ± 5.8 (range: 1.1–28.6) cm2. All subjects were placed on systemic antibiotics for at least 6 weeks in conjunction with baseline application of TTAX01. Repeat applications were made at no less than 4‐week intervals over the 16‐week trial. Initial closure occurred in 18 of 32 (56%) wounds, with 16 (50%) of these having confirmed closure in 16 weeks with a median of one‐product application. Cases with biopsy confirmed osteomyelitis (n = 20) showed initial closure in 12 (60%) wounds and confirmed closure in 10 (50%) wounds. Four of the five ulcers presenting as recurrences experienced confirmed closure. Mean overall time to healing was 12.8 ± 4.3 weeks. Mean wound area reduction from baseline was 91% for all wounds. Of the 16 wounds without confirmed closure during the 16‐week treatment period, five (31.3%) achieved 99–100% wound area reduction by their final visit. The product was well tolerated. Two minor amputations occurred during the study period due to recurrent or persistent osteomyelitis; however, there were no major amputations.

Objective: The objective of this study was to characterize factors associated with closure of venous leg ulcers (VLUs) in a pooled analysis of subjects from three randomized clinical trials. Methods: Closure of VLUs after treatment with HP802-247, an allogeneic living cell therapy consisting of growth-arrested human keratinocytes and fibroblasts, vs standard therapy with compression bandaging was evaluated in three phase 3 clinical trials of similar design. Two trials enrolled subjects with VLUs ranging from 2 cm 2 to 12 cm(2) to 12 cm(2) in area with 12-week treatment periods; the third trial enrolled subjects with VLUs between >12 cm(2) and <= 36cm(2) with a 16-week treatment period. The first trial went to completion but failed to demonstrate a benefit to therapy with HP802-247 compared with placebo, and because of this, the remaining trials were terminated before completion. On the basis of no differences in outcomes between groups, subjects from both HP802-247 and control groups were pooled across all three studies. Cox proportional hazards regression analysis was employed to evaluate factors associated with VLU closure. Results: This analysis included data from 716 subjects with VLU. Factors evaluated for association with healing included age, gender, race, diabetes, glycated hemoglobin level, body mass index, treatment (HP802-247 vs compression alone), and ulcer characteristics including location and area and duration at baseline. In an initial model including all of these putative factors, the following were significant at the P < .10 level: diagnosis of diabetes mellitus, gender, wound location (ankle or leg), baseline wound area, and wound duration at baseline. In a final model including only these factors, all but diabetes mellitus were significant at the P< .05 level. Effect sizes were as follows (hazard ratio [95% confidence interval]): female gender (1.384 [1.134-1.690]), wound location on the leg (1.490 [1.187-1.871]), smaller wound area at baseline (0.907 [0.887-0.927]), and shorter wound duration at baseline (0.971 [0.955-0.987]). Conclusions: Factors associated with VLU lesions including location, area, and duration were important predictors of healing. Women were more likely than men to achieve wound closure. Factors including body mass index, the presence of diabetes mellitus, and higher concentrations of glycated hemoglobin were not significant independent predictors of wound closure in this analysis.

Venous leg ulcers (VLUs) are the most common cause of leg ulcers (Alavi et al., 2016) affecting 2.2% of Americans 65 years of age and older (Heit et al., 2001) and are costly as they account for an estimated cost of nearly $15 billion annually in the US health care system (Rice et al., 2014). Depending in part on ulcer size and duration, 40–75% of patients heal with standard care using compression therapy. As an adjunct to compression, certain medications, for example aspirin (Varatharajan et al., 2014), pentoxifylline (Jull et al., 2012), and statins (Evangelista et al., 2014), have been shown to improve healing in randomized controlled trials (RCTs) (Alavi et al., 2016).

Objective. The aim of this randomized, controlled multicenter trial was to evaluate the clinical outcomes associated with the use of clostridial collagenase ointment (CCO) for up to 12 weeks in 215 patients with type 1 or type 2 diabetes mellitus and a neuropathic, nonischemic diabetic foot ulcer (DFU). Materials and Methods. Patients were randomized into either a group receiving CCO applied once daily at a thickness of 2 mm or a group receiving standard care (SC) consisting of a daily application of a hydrogel as needed to maintain a moist ulcer environment. All ulcers were covered with a nonadherent foam dressing that was changed once daily, and sharp debridement was allowed when the investigators deemed it medically warranted. Outcome measures included the percent change in ulcer area and the effect of baseline wound microbiota on subsequent healing. Patients with ulcers that showed no decrease in size after 4 weeks were crossed over to the other treatment group. Results. The wound area decreased relative to baseline for both the CCO group (-60%, P <.0001;-65%, P <.0001) and the control group (-50%, P=.0001;-51%, P=.0001) after 6 and 12 weeks, respectively. While the intergroup differences at 6 and 12 weeks did not reach statistical significance (P =.3801; P =.3606), mean percent reductions for the CCO group were greater than the control at all 12 time points (averages:-55%;-41%, respectively). Overall closure rate was 21% and 41% (weeks 6 and 12, P =.3705; P =.2358) with no significant differences between groups. However, the DFUs that showed no improvement at 4 weeks (N = 24, 12/group) were crossed over to the other treatment group. A numerically greater proportion of subjects who switched to CCO achieved closure (33%) than for those who switched to SC (8%). Baseline biopsy showed that despite the absence of clinical signs of infection, all ulcers were heavily colonized by 1 to 5 species of bacteria. No adverse events were assessed by the investigators as related to either treatment. Conclusion. These results confirm observations from previous studies demonstrating positive outcomes associated with enzymatic debridement with CCO following 6 weeks of treatment.

Venous leg ulcers (VLUs) are the most prevalent type of leg ulcer in the US. Better understanding of factors associated with healing is needed. We performed a secondary analysis of 3 phase 3 multi-center trials that studied a novel cell therapy for refractory VLU, which was ineffective. Patients with non-healing VLUs that failed to improve with standard compression were studied. The trials endpont was closure by 12 weeks. We focused on evaluating the relationship between various systemic medications and VLU healing. Chi-square and logistic regression analysis were performed. Complete data from 715 of 884 patients enrolled in the trials was used. Using logistic regression the only association with not healing by week 12 was Opioid use (OR 0.64, (95% CI:0.46,0.88), p=0.006). Larger ulcer area, longer duration of ulcer, and being male were also associated with non-healing but in an adjusted model did not confound the opioid effect (adjusted OR 0.69 (0.49,0.97), p=0.035). The mechanism by which opioids may impair healing is not known but opioids inhibit substance P, which modules mesenchymal stem cells and IL-8 expression. Other possible mechanisms include reduced neutrophil, macrophage and myofibroblast recruitment, decreased angiogenesis, and altered keratinocyte cytokine production. Alternatively opioid usage may be a marker of unmeasured confounders associated to poor healing, e.g. hygiene, nutrition, exercise, or other (undocumented) drugs. We did not find an association between VLU healing and use of other medications. However, study design might have excluded patients who responded to these therapies as the studies focused on a refractory subset of VLUs.

In 2012 we reported promising results from a phase 2 clinical trial of HP802-247, a novel spray-applied investigational treatment for chronic venous leg ulcers consisting of human, allogeneic fibroblasts and keratinocytes. We now describe phase 3 clinical testing of HP802-247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802-247 to show efficacy in these two phase 3 trials was initiated immediately following the initial review of the North American trial results. Four hundred twenty-one patients were enrolled in the North American (HP802-247, 211; Vehicle 210) and 252 in the European (HP802-247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802-247, 61.1%; Vehicle 60.0%; p=0.5896) or the European (HP802-247, 47.0%; Vehicle 50.0%; p=0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802-247. Concordance between the two separate, randomized, controlled trials with distinct, nonoverlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Slade H, Jacobson N, Lu Y. Human cell therapy for venous leg ulcers. Phlebological Review. 2015;23(2):29-38. doi:10.5114/pr.2015.54032. APA Slade, H., Jacobson, N., & Lu, Y. (2015). Human cell therapy for venous leg ulcers. Phlebological Review, 23(2), 29-38. https://doi.org/10.5114/pr.2015.54032 Chicago Slade, Herbert B., Nasreen Jacobson, and Yiling Lu. 2015. "Human cell therapy for venous leg ulcers". Phlebological Review 23 (2): 29-38. doi:10.5114/pr.2015.54032. Harvard Slade, H., Jacobson, N., and Lu, Y. (2015). Human cell therapy for venous leg ulcers. Phlebological Review, 23(2), pp.29-38. https://doi.org/10.5114/pr.2015.54032 MLA Slade, Herbert B. et al. "Human cell therapy for venous leg ulcers." Phlebological Review, vol. 23, no. 2, 2015, pp. 29-38. doi:10.5114/pr.2015.54032. Vancouver Slade H, Jacobson N, Lu Y. Human cell therapy for venous leg ulcers. Phlebological Review. 2015;23(2):29-38. doi:10.5114/pr.2015.54032.

Objective: This study demonstrates that superior outcomes are possible when diabetic foot ulcers (DFU) are managed with tri-layer porcine small intestine submucosa (SIS). Approach: Patients with DFU from 11 centers participated in this prospective randomized controlled trial. Qualified subjects were randomized (1:1) to either SIS or standard care (SC) selected at the discretion of the Investigator and followed for 12 weeks or complete ulcer closure. Results: Eighty-two subjects (41 in each group) were evaluable in the intent-to-treat analysis. Ulcers managed with SIS had a significantly greater proportion closed by 12 weeks than for the Control group (54% vs. 32%, p=0.021) and this proportion was numerically higher at all visits. Time to closure for ulcers achieving closure was 2 weeks earlier for the SIS group than for SC. Median reduction in ulcer area was significantly greater for SIS at each weekly visit (all p values<0.05). Review of reported adverse events found no safety concerns. Innovation: These data support the use of tri-layer SIS for the effective management of DFU. Conclusion: In this randomized controlled trial, SIS was found to be associated with more rapid improvement, and a higher likelihood of achieving complete ulcer closure than those ulcers treated with SC.

To the Editor: Thomas Serena et al. and the EpiFix VLU Study Group have reported what appear to be very good outcomes achieved in the healing of venous leg ulcers (VLU) when treated with dehydrated human amnion/chorion membrane (dHACM) used in conjunction with standard multilayer compression. New approaches are badly needed as many people suffering with VLU are not healed with standard compression therapy alone. While we agree that the use of an extracellular matrix product derived from placental tissues is certainly of interest, several aspects of the study design raise concerns that we feel require the results of this study to be interpreted with caution. We offer the following considerations in the spirit of constructive criticism. Our view is that better trial designs with clear conclusions will allow those suffering with VLU to have the best chance of success with advanced therapeutic options. It is well known that between 30 and 75 % of all VLU will respond to standard compression therapy and heal. Those VLU that do not respond become chronic and represent the unmet medical need. A novel therapy, such as dHACM, designed to improve upon standard care (i.e., multilayer compression bandaging) should be tested in the population it is intended to benefit, namely, chronic ulcers that have failed to respond to compression. One way to accomplish this is to employ a run-in period prior to randomization where the rate of healing is monitored under compression alone. VLU that respond during this period should not be randomized, ensuring that only the nonresponsive, chronic ulcers are enrolled. In this study there was a requirement for ulcers to have been treated for 2 weeks with compression therapy; however, inexplicably, there were no exclusions for rapid healers. To the contrary, ulcers that had been nonhealing under 1 year of compression were excluded from the trial. It is also well known that small ulcers heal more rapidly and successfully than large ulcers. The minimum eligible ulcer size is given as 2 cm in the published paper, but as 5 cm in the clinicaltrials.gov posting (NCT01552447). The median size enrolled was 4.4 cm for the dHACM group and 4.1 cm for compression, thus half of the ulcers across the study were 4 cm or less and relatively easy to heal. Taken together, it would seem that the study population likely included small, rapid-healing ulcers and excluded many of the chronic ulcers that were the aim of the study. Our greatest concern lies in the choice of endpoint. The only valid endpoint recognized by the Food and Drug Administration (FDA) and other regulatory bodies is ulcer closure defined as 100% reepithelialized, without drainage and not requiring a dressing. Moreover, this closure must be confirmed at two subsequent visits, each at 2-week intervals. Instead, the authors chose the surrogate endpoint of 40% wound closure at 4 weeks. While there is some literature suggesting that this may be a good predictor of ultimate healing at 12 or 24 weeks, the same literature acknowledges that it is only correct about 70% of the time. Taking this 70% accuracy and applying it to the 62% of ulcers achieving a 40% reduction in area by week 4 (0.62 × 0.7), an estimated 43% would have been closed at 12 weeks. As the authors did not validate this endpoint by following the patients for a full 12 weeks, this seems to be the most reasonable conclusion. The problems with this paper are not limited to the study population and the primary endpoint, but also include patient bias and inaccurate wound area measurements. Ulcer pain was a stated secondary endpoint and was assessed using the visual analog scale (VAS). While this is a standard method, it is inherently subjective and therefore susceptible to patient bias. Patients were not blind to treatment and, as noted in the paper, three patients randomized to compression alone withdrew from the study because they were unhappy with the treatment assignment, suggesting that patients viewed the control group as an inferior treatment. Ulcer area and not closure was the primary endpoint in this trial, therefore there was a critical need for accurate measurement of the ulcers. While ruler measurements may be adequate for “real world” ulcer management, digital wound measurement devices have become the standard in sponsored clinical trials. It is disappointing that area was assessed as length × width using a ruler. While we agree that dHACM is an interesting treatment that may provide a benefit for healing chronic VLU, this has not been demonstrated with any surety in the current trial. Additional studies with the appropriate patient population and appropriate endpoints are needed.

BACKGROUND:Digestion of collagen with clostridial collagenase (CC) produces peptides that can induce cellular responses consistent with wound healing in vivo. However, nonhealing human wounds are typically in a state of chronic inflammation. We evaluated the effects of CC on markers of inflammation in cell culture and wound fluid from diabetic patients.METHODS:Lipopolysaccharide-induced release of tumor necrosis factor-α and interleukin-6 from interferon-γ-activated THP-1 monocytes was measured in the presence or absence of CC or CC collagen digests. In the clinical study, 17 individuals with mildly inflamed diabetic foot ulcers were randomized to receive CC ointment (CCO) or hydrogel. Weekly assessments included wound appearance and measurements. Wound exudate was collected at baseline and at 2 and 4 weeks of treatment. A multiplex assay was used to measure levels of analytes, including those associated with inflammation and with inflammation resolution.RESULTS:Lower levels of tumor necrosis factor-α and interleukin-6 were found in media of cells cultured with CC or CC digests of collagen type I or III than for untreated lipopolysaccharide controls (P < .05). Clinically, CCO and hydrogel resulted in improvement in wound appearance and a decrease in mean wound area. The CCO, but not the hydrogel, was found to increase the level of analytes associated with resolution of inflammation while decreasing those associated with inflammation. There was a general correlation between resolution of inflammation and healing.CONCLUSIONS:These results support a hypothesis that debridement with CCO is associated with decreased inflammation and greater progress toward healing.

Background Digestion of collagen with clostridial collagenase (CC) produces peptides that can induce cellular responses consistent with wound healing in vivo. However, nonhealing human wounds are typically in a state of chronic inflammation. We evaluated the effects of CC on markers of inflammation in cell culture and wound fluid from diabetic patients. Methods Lipopolysaccharide-induced release of tumor necrosis factor-α and interleukin-6 from interferon-γ–activated THP-1 monocytes was measured in the presence or absence of CC or CC collagen digests. In the clinical study, 17 individuals with mildly inflamed diabetic foot ulcers were randomized to receive CC ointment (CCO) or hydrogel. Weekly assessments included wound appearance and measurements. Wound exudate was collected at baseline and at 2 and 4 weeks of treatment. A multiplex assay was used to measure levels of analytes, including those associated with inflammation and with inflammation resolution. Results Lower levels of tumor necrosis factor-α and interleukin-6 were found in media of cells cultured with CC or CC digests of collagen type I or III than for untreated lipopolysaccharide controls (P < .05). Clinically, CCO and hydrogel resulted in improvement in wound appearance and a decrease in mean wound area. The CCO, but not the hydrogel, was found to increase the level of analytes associated with resolution of inflammation while decreasing those associated with inflammation. There was a general correlation between resolution of inflammation and healing. Conclusions These results support a hypothesis that debridement with CCO is associated with decreased inflammation and greater progress toward healing.

INTRODUCTION:Clinical models are invaluable in studying wound healing. Challenges in studying human wounds include heterogeneity of patients and wounds, as well as prolonged study time, resulting in high costs. Animal models are an efficient method to study wound healing, but often lack correlation with human acute wound healing. Human wound models can be created using sharp instruments, suction, acids, heat and cold. In this observational study, we propose a practical human acute wound model where partial thickness wounds are induced by cryosurgery to create wounds that could facilitate wound healing research and development.METHODS:On forearms of 8 healthy adult volunteers, freeze injuries were induced using liquid nitrogen spray delivered onto a target area of a 1 cm circular opening at a distance from the cryo-device to the skin of 0.5-1 cm. Several freeze-thaw time cycles were implemented by administering pulses ranging from 3 to 12 seconds. Clinical evaluation was performed at a 24-hour follow-up period. Blister roofs were histologically analyzed by a blinded dermatophathologist. Clinical assessment of time to heal was determined.RESULTS:Freeze-times greater than 5 seconds caused a majority of subjects to develop blisters, and freeze-times greater than 8 seconds resulted in uniform blister formation. Consistent histology of full thickness necrotic epidermis with intact detached basement membrane with minimal acute neutrophilic inflammatory infiltrate was observed in all blister specimens examined. The 8-second freeze-time group had a time to heal of 13-14 days, while the 12-second freeze-time group required 3 weeks to heal. After healing, an area of hypopigmented skin and slightly hypertrophic scarring remained.DISCUSSION:This novel cryo-induced wound model is a potential simple, efficient and reliable model for studying the dynamic processes involved in acute wound healing and to aid in the development of new wound healing therapies. Clinicaltrials.gov identifier: NCT01253135.

ABSTRACT Resiquimod, a Toll-like receptor 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 acquired immune response. Animal and phase II human trials showed posttreatment efficacy in reducing recurrent herpes lesion days and/or time to first recurrence. Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod to reduce anogenital herpes recurrences were conducted in healthy adults with ≥4 recurrences within the prior year. Participants applied resiquimod 0.01% gel or vehicle gel 2 times per week for 3 weeks to each recurrence for 12 months. Trials 1 and 2 had 2:1 resiquimod-vehicle randomization. Trial 3 had 1:1:1 randomization for resiquimod and 500 mg valacyclovir orally twice daily for 5 days (RESI-VAL), resiquimod and oral placebo (RESI-PLA), and vehicle and oral placebo (VEH-PLA). The median time to first recurrence was similar for resiquimod and vehicle (trial 1, 60 and 56 days, P = 0.7; trial 2, 54 and 48 days, P = 0.47; trial 3, 51 [RESI-VAL], 55 [RESI-PLA], and 44 [VEH-PLA] days, P = not significant [NS]). The median time to healing of initial treated recurrence was longer for resiquimod (trial 1, 18 compared to 10 days, P < 0.001; trial 2, 19 compared to 13 days, P = 0.16; trial 3, 14 [RESI-VAL], 16 [RESI-PLA], and 8 [VEH-PLA] days, P < 0.001). In trials 1 and 2, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. In conclusion, no posttreatment efficacy of resiquimod 0.01% gel was observed. Increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects.

Objective. Fifty-five subjects with diabetes mellitus type 1 or 2 and a neuropathic, nonischernic foot ulcer were enrolled into this randomized, controlled, multicenter trial designed to examine the effects of debridement with clostridial collagenase ointment (CCO) used in conjunction with serial sharp debridement for a period of 6 weeks. Methods. Serial sharp debridement without adjunctive COO was used in the control group. Various standard care therapies thought to support debridement by endogenous proteases were selected at the discretion-of the investigators for use in the control group. The primary outcome measure of this trial was the percent change in ulcer area from baseline at the end of the debridement/treatment period (EOT) and at the end of an additional 6 weeks of follow-up (EOS). Secondary objectives were to assess wound status at EOT and EOS using a Standardized wound assessment tool, and to compare the average time to closure for ulcers debrided with serial sharp debridement with and without adjunctive COO:, Results. Wound area decreased relative to baseline for both the CCO group (-68%, -61%) and the control group (-36%, -46%) at EOT and EOS, respectively. While the inter-group differences did not reach statistical significance, wound area was significantly decreased from baseline at both EOT and EOS for the COO (P < 0.001) but not for the control group. Wound Status Scores (scale range 8 to 40) improved for both groups during treatment (CCO: -3.5, control:,-3.2) and follow-up (000: control: -6.4). No differences were observed in the number of sharp debridements (COO: 3.7, control: 4.0). Median time to closure for wounds That healed Was 6 weeks for CCO and 8 weeks for control On average, ulcers treated with Serial sharp debridernent plus adjunctive CO decreased in sin more rapidly than ulcers treated without adjunctive CCO debridement. No safety issues were identified based on a review of reported adverse events.' Conclusion. These :results Suggest there is more to wound,debridement than meets the eye, and establish a foundation for larger, confirmatory studies.

Limitation of ankle movement may contribute to calf muscle pump failure, which is thought to contribute to venous leg ulcer formation, which affects nearly 1 million Americans. We therefore wished to study ankle movement in patients with venous leg ulcers and its effect on healing. Using goniometry, we measured baseline ankle range of motion in venous leg ulcer patients from a Phase 2 dose-finding study of an allogeneic living cell bioformulation. Two hundred twenty-seven patients were enrolled in four active treatment groups and one standard-care control group, all receiving compression therapy. Goniometry data from a control group of 49 patients without venous disease, from a previous study, was used for comparison. We found patients with active venous leg ulcers had significantly reduced ankle range of motion compared with the control group (p = 0.001). After 12 weeks of therapy, baseline ankle range of motion was not associated with healing, as there was no significant difference between healed and nonhealed groups, suggesting that ankle range of motion is not important in venous leg ulcer healing or, more likely, is overcome by compression. However, patients with venous ulcers located on the leg (as opposed to the ankle) had significantly higher ankle range of motion for plantar flexion and inversion (p = 0.021 and p = 0.034, respectively) and improved healing with both cell bioformulation and standard care (p = 0.011), suggesting that wound location is an important variable for ankle range of motion as well as for healing outcomes.