Deferoxamine Intradermal Delivery Patch for Treatment of a Beta-Thalassemia Wound.

MINI-ABSTRACT: In this study, we present the first-in-human use of topical deferoxamine (DFO) in the treatment of a beta-thalassemia wound. We elected to use DFO on a patient that suffered from a chronic nonhealing wound in the setting of beta-thalassemia. Despite approximately 55 weeks of marginal improvement in healing, this patient's wound healed completely after 21 weeks of treatment with DFO. We believe that DFO has the potential to accelerate healing in beta-thalassemia wounds through iron chelation.

Long-Term Results of Suture-Button Suspensionplasty in the Treatment of Thumb Carpometacarpal Arthritis: A Minimum 10-Year Follow-Up.

Purpose: Combined trapeziectomy and suture-button suspensionplasty (SBS) is a common and well-established surgical treatment for thumb carpometacarpal (CMC) osteoarthritis. Although short and mid-term follow-up studies have shown promising outcomes with patients retaining excellent range of motion and strength, long-term data are lacking. The aim of our study was to assess the long-term outcomes of patients who underwent SBS surgery for thumb CMC arthritis, with a minimum follow-up period of 10 years. Methods: We evaluated 17 patients, at least 10 years after undergoing SBS surgery for thumb CMC arthritis. We measured grip and pinch strength, range of motion, and trapezial space height and compared it with the respective values measured on the routine postoperative 3-month follow-up visit. All patients have additionally completed the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire. Results: The study included 11 women and 6 men with an average age of 60.3 ± 6.4 years and a mean follow-up of 137.4 ± 11.4 months after surgery. The mean Quick Disabilities of the Arm, Shoulder, and Hand score was 9 (range: 0-40.9) at the long-term follow-up, compared with 26.2 (range: 4.5-75) recorded 3 months after the surgery. Grip and pinch strengths were 116% and 111% of the 3-month postoperative value, respectively. Radial abduction and palmar abduction were 98% and 94% of the 3-month postoperative value, respectively. Kapandji scores were either equal or higher than the previously documented scores. Average height of the trapezial space was 69% of the previous postoperative measurement. Conclusions: Our findings demonstrate that patients who underwent SBS surgery for thumb CMC osteoarthritis achieve excellent long-term outcomes by maintaining favorable subjective and objective results, despite some radiographic subsidence over time. These results indicate SBS to be an effective and durable technique for the long-term management of thumb CMC osteoarthritis. Type of study/level of evidence: Therapeutic IV.

Multidisciplinary Extremity Preservation Program Improves Quality of Life for Patients with Advanced Limb Threat.

BACKGROUND: The need for multidisciplinary care of patients with advanced limb threat is well established. We examined patient reported outcomes and health-related quality of life (HR-QoL) for those who completed a multidisciplinary extremity preservation program (EPP) at our institution. METHODS: Patients with advanced limb threat, who had previously failed standard management at a tertiary-care center, were referred to EPP for evaluation by a multidisciplinary panel of vascular, plastic, orthopedic and podiatric surgeons, along with infectious disease, prosthetics, orthotics, imaging, palliative care, social work and wound nursing specialists. HR-QoL was quantified before and after EPP participation with the RAND-36 questionnaire. The validated RAND-36 assesses physical function, role limitations caused by physical and emotional health problems, social functioning, emotional well-being, energy, pain and general health perceptions. RESULTS: From 2018 to 2020, 185 patients were referred to EPP. After review by the multidisciplinary panel, 120 were accepted into the program, 63 of whom completed their course of care; 9 were one-time consultations. The median number of EPP in-person care visits was 23 (13-54) per participant; 87.3% of patients received one or more surgical procedure, including operative debridement (73%), revascularization (44%), soft-tissue reconstruction or transplantation (46%), as well as hyperbaric oxygen therapy (11%) during their course of treatment. 85.7% of patients achieved complete wound healing, 41.5% occurring within 6 months. Ultimately, 14.3% required a major amputation. Graduates noted improvement in all categories of the HR-QoL upon completion, including those undergoing major amputation. On adjusted multivariate regression analysis, patients with immunocompromised status were more likely to show greater improvement in their social function (OR: 10.1; P < 0.044) and emotional role limitation (OR: 8.1; P = 0.042), while, patients with larger wound volume at presentation were more likely to have greater improvement in their general health (OR: 1.1; P < 0.049). Conversely, patients with a smoking history had less improvement in energy level (OR: 0.4; P = 0.044) and patients with dialysis-dependence had less improvement in social function (OR: 0.2; P = 0.034). CONCLUSIONS: Coordinated, multidisciplinary extremity preservation program improves HR-QoL of patients with complex limb threat, including those who are immunocompromised with impaired social function and emotional role limitations. Furthermore, study is warranted to better characterize the generalizability of this approach, including considerations of cost-effectiveness, wound recidivism, and limiting the number of in-person visits required to achieve complete healing.

Six-Month Outcomes of Reimplantation of a Coin-Sized Tibial Nerve Stimulator for the Treatment of Overactive Bladder Syndrome With Urgency Urinary Incontinence.

OBJECTIVE: The eCoin (Valencia Technologies Corporation, Valencia, CA) is a battery-powered, nickel-sized and shaped neuromodulation device for the treatment of overactive bladder, and it is implanted in the lower leg in a short office or outpatient procedure under local anesthesia. A follow-on trial was conducted to evaluate the feasibility, safety, and efficacy of eCoin reimplantation. METHODS: This was a prospective, single-arm, open-label study, including 23 participants with refractory urgency urinary incontinence (UUI) who were previously participants in the eCoin clinical feasibility trial. This follow-on study was conducted at 7 sites in the United States and New Zealand. Participants were reimplanted with a new eCoin device and activated after 4 weeks. Bladder diary data and validated quality-of-life instruments, collected at 12 weeks and 24 weeks postactivation, were compared with baseline. RESULTS: Participants of the study were considered responders if they reported a ≥ 50% reduction from baseline in episodes of UUI on a 3-day voiding diary. At 12 weeks of treatment, 74% (95% confidence interval [CI], 52%-90%) of participants were considered responders. At 24 weeks of treatment, 82% (95% CI, 60%-95%) of participants were considered responders with 36% (95% CI, 20%-57%) of participants achieving complete continence. There were no device-related serious adverse events reported during the study. CONCLUSIONS: The reimplantation of eCoin was both safe and effective in treating UUI associated with overactive bladder syndrome. The demonstrated significant reduction or resolution of symptoms with no serious safety concern suggests that eCoin is a convenient and maintainable therapeutic device.

Twelve-month Durability of a Fully-implanted, Nickel-sized and Shaped Tibial Nerve Stimulator for the Treatment of Overactive Bladder Syndrome with Urgency Urinary Incontinence: A Single-Arm, Prospective Study.

OBJECTIVES: To evaluate the safety and efficacy of the eCoin - a nickel-sized, primary battery-powered, neuromodulation device for the treatment of urgency urinary incontinence which is implanted in the lower leg in a 20-minute procedure under local anesthesia. A feasibility clinical trial was conducted and the results after 1 year of treatment with the eCoin are presented. METHODS: A total of 46 participants with refractory urgency urinary incontinence were included in this prospective, single-arm, open-label study. This study was conducted at 7 sites in the United States and New Zealand. Participants in this study were implanted with the eCoin in the lower leg over the tibial nerve and activated after 4 weeks. Bladder diary data and validated quality-of-life instruments, collected at 3, 6, and 12 months' post-activation, were compared to baseline values. RESULTS: Responders were defined as those who had a ≥50% reduction in reported episodes of urgency urinary incontinence. At 12 months', 65% of participants were considered responders with 26% of participants achieving complete continence. The median number of urgency urinary incontinence episodes per day decreased from 4.2 at baseline to 1.7 at 12 months'. Seventy percent of participants reported feeling "better", "much better", or "very much better" on the Likert 7-point maximum scale. One participant experienced a related serious adverse event. CONCLUSION: The eCoin is a safe and effective treatment for urgency urinary incontinence associated with overactive bladder syndrome, with significant reduction or complete resolution of symptoms and no significant safety concerns.

Feasibility of a Fully Implanted, Nickel Sized and Shaped Tibial Nerve Stimulator for the Treatment of Overactive Bladder Syndrome with Urgency Urinary Incontinence.

PURPOSE: We performed a clinical feasibility trial to evaluate the safety and efficacy of a fully implanted, primary battery powered, nickel sized and shaped neuromodulation device called the eCoin® for tibial nerve stimulation to treat refractory urgency urinary incontinence. MATERIALS AND METHODS: This prospective, single arm, open label study included 46 participants with refractory urgency urinary incontinence. It was performed at multiple sites in the United States and New Zealand. The device was implanted in the lower leg over the tibial nerve and activated after 4 weeks. Bladder diary data and validated quality of life instruments were collected 3 and 6 months after activation and compared to baseline values. RESULTS: The mean ± SD age of participants was 63.4 ± 11.5 years and 45 (98%) were female. Episodes of urgency urinary incontinence were reduced a relative median of 71% after 3 months of treatment (4.2 vs 1.7 daily episodes at 3 months, p = 0.001). A 50% or greater decrease in reported episodes of urgency urinary incontinence was observed in 32 of 46 participants (69.6%) at 3 months with more than 20% dry at 3 and 6 months. I-QOL (Incontinence Quality of Life) scores improved an average of 25.9 points and 33 of 46 patients (72%) indicated improvement in symptoms. A single serious adverse event secondary to wound care resolved with intravenous antibiotics. CONCLUSIONS: The implantable neuromodulation device was a safe and effective treatment of urgency urinary incontinence associated with overactive bladder syndrome with a significant reduction or resolution of symptoms and no significant safety concerns.

Comparing Muscle and Fasciocutaneous Free Flaps in Lower Extremity Reconstruction--Does It Matter?

INTRODUCTION: Plastic surgeons are often asked to assist with the reconstruction of lower extremity wounds. These patients many times require free tissue transfer for coverage given paucity of soft tissue. Anecdotally, many orthopedic surgeons prefer muscle coverage--particularly in the setting of potentially infected bone. Today's surgeons now easily harvest and transfer fasciocutaneous flaps--a versatile option with less donor-site morbidity. We hypothesized that there would be no difference in outcomes between these 2 types of reconstruction. METHODS: We performed a single-institution retrospective review of lower extremity free flap reconstructions in the last 10 years. Demographics, preoperative and postoperative course, and the documented time to weight-bearing and bony union were collected. Major cohorts compared were muscle free flaps and fasciocutaneous free flaps, further divided into subgroups including acute trauma, tumor resection, osteomyelitis, and nonunion. Data comparisons were made using paired t test and Fischer exact tests. RESULTS: There were 121 patients who met inclusion criteria--86 in the muscle flap group, and 35 in the fasciocutaneous group and demographics were equal. Total complication rates were higher in smokers than nonsmokers (P < 0.03). There was no significant difference in major or minor complication rates between muscle and fasciocutaneous flaps in any subgroup. In both the acute fracture group and the infected nonunion group, there was a significantly faster return to weight bearing in the fasciocutaneous group (P < 0.03) although there was no difference in documented time to bony union. Patients who underwent fasciocutaneous reconstruction were more likely to require revisionary surgery for improved aesthetics (P < 0.001). CONCLUSIONS: Our data suggest that in essentially all clinical parameters, there is no difference between free flap type used for soft tissue coverage of the lower extremity. Patients undergoing reconstruction with a fasciocutaneous flap may return to weight bearing earlier--although they are more likely to require elective flap revisions. These results imply essentially equivalent outcomes regardless of flap type or operative indication, in contrast with some of the biases in the orthopedic community. The particular flap chosen for any reconstruction should remain solely at the discretion of the plastic surgeon.

Injuries to appendage extremities and digit tips: A clinical and cellular update.

BACKGROUND: The regrowth of amputated appendage extremities and the distal tips of digits represent models of tissue regeneration in multiple vertebrate taxa. In humans, digit tip injuries, including traumatic amputation and crush injuries, are among the most common type of injury to the human hand. Despite clinical reports demonstrating natural regeneration of appendages in lower vertebrates and human digits, current treatment options are suboptimal, and are complicated by the anatomical complexities and functions of the different tissues within the digits. RESULTS: In light of these challenges, we focus on recent advancements in understanding appendage regeneration from model organisms. We pay special attention to the cellular programs underlying appendage regeneration, where cumulative data from salamanders, fish, frogs, and mice indicate that regeneration occurs by the actions of lineage-restricted precursors. We focus on pathologic states and the interdependency that exists, in both humans and animal models, between the nail organ and the peripheral nerves for successful regeneration. CONCLUSIONS: The increased understanding of regeneration in animal models may open new opportunities for basic and translational research aimed at understanding the mechanisms that support limb regeneration, as well as amelioration of limb abnormalities and pathologies.

Changing attitudes toward hand allotransplantation among North American hand surgeons.

OBJECTIVES: Although more than 70 hand transplants have been performed worldwide, the appropriate clinical indications for this operation are still being determined. Cost and patient exposure to the challenges of lifelong immunosuppression for what is a quality of life-improving (but not life-saving) operation are the focus of the ongoing discussion. A study performed in 2007 showed that surgeons' opinions on the issue varied widely. Recently, more information has been made available regarding long-term patient outcomes, and significant improvements in immunotherapy protocols have been reported. In light of this, we sought to examine changing attitudes regarding hand allotransplantation and its indications by surveying hand surgeons. METHODS: An email-based survey was sent to members of the American Society for Surgery of the Hand. Demographic information and practice profiles were identified, followed by their risk assessment of hand allotransplants and endorsement of performing the operation in different clinical scenarios. Additional questions focused on the appropriate indications for hand allotransplantation, as well as the procedure's associated ethical and financial implications. RESULTS: A total of 385 surgeons responded to the survey (14% response rate). The majority (82%) considered hand transplantation to be a high-risk operation (as opposed to 27% in hand replantation), with 78% citing lifelong immunosuppression as the primary factor impacting their overall risk assessment. The most commonly accepted indication for hand vascularized composite allotransplantation was loss of bilateral hands (80% in favor). Dominant hand loss (with an intact contralateral hand) was a far less frequently accepted indication (36% in favor). Patient adherence to immunosuppressive regimens (51%) and expectations of functional/aesthetic outcome (38%) were the most frequently chosen top psychosocial issues that must be addressed by the surgical/medical teams involved in the operation. CONCLUSIONS: Our study's results demonstrate increasing overall support for hand allotransplantation and increasing acceptance of today's immunosuppressive regimens compared to prior literature. Bilateral hand loss remains the primary agreed-upon indication for transplantation. Despite increasing acceptance in the surgical community, the dangers of chronic immunosuppression, cost and patient adherence continue to be the primary concerns hindering its broader acceptance.

Fascia-only anterolateral thigh flap for extremity reconstruction.

INTRODUCTION: The ability to use the anterolateral thigh (ALT) flap as a vascularized fascial flap, without skin or muscle, was first documented by Koshima et al in 1989. The authors mention the possibility of using the fascia alone for dural reconstruction. Despite its description more than 20 years ago, little literature exists on the application of the ALT flap as a vascularized fascial flap. In our experience, the ALT flap can be used as a fascia-only flap for thin, pliable coverage in extremity reconstruction. METHODS: After approval from the institutional review board, the medical records and photographs of patients who had undergone fascia-only ALT free flaps for extremity reconstruction were reviewed. Photographic images of patients were then matched to patients who had undergone either a muscle-only or a fasciocutaneous free flap reconstruction of an extremity. Photographs of the final reconstruction were then given to medical and nonmedical personnel for analysis, focusing on aesthetics including color and contour. RESULTS: Review of cases performed over a 2-year period demonstrated similar ease of harvest for fascia-only ALT flaps compared to standard fasciocutaneous ALT flaps. Fascia-only flaps were used for thin, pliable coverage in the upper and lower extremities. There was no need for secondary procedures for debulking or aesthetic flap revision. In contrast to muscle flaps, which require muscle atrophy over time to achieve their final appearance, there was a similar flap contour from approximately 1 month postoperatively throughout the duration of follow-up. When a large flap is required, the fascia-only ALT has the advantage of a single-line donor-site scar. Photograph comparison to muscle flaps with skin grafts and fasciocutaneous flaps demonstrated improved color, contour, and overall aesthetic appearance of the fascia-only ALT over muscle and fasciocutaneous flaps. CONCLUSIONS: The fascia-only ALT flap provides reliable, thin, and pliable coverage with improved contour and color over muscle and fasciocutaneous flaps. The fascia-only ALT is another excellent option for reconstructive surgery of the extremities.

Assessment of the immune response to dose of nerve allografts.

Nerve allotransplantation provides a limitless source of nerve graft material for the reconstruction of large neural defects. It does require systemic immunosuppression or induction of immune unresponsiveness to prevent allograft rejection. It is unknown whether a greater volume of nerve graft material will increase the risk of rejection or the need for more intensive immunosuppression. This study assessed the relationship between the quantity of nerve tissue transplanted and the magnitude of the resulting immune response. Forty female (BALB/c) mice were randomly assigned to two groups that received either nerve isografts (BALB/c) or nerve allografts (C57BL/6). Each group was then subdivided into two groups that received either one or 10 sciatic nerve graft inlays. Histological and immunological assessments were performed at 10 days after engraftment. Histologic analysis demonstrated greater cellular infiltration in the allograft than the isograft groups but no appreciable difference in infiltration related to quantity of transplanted nerve tissue. In vitro assessments of the immune response using mixed lymphocyte assays and limiting dilution analysis similarly demonstrated a robust immune response to allografts but no effect on quantity of transplanted nerve tissue. These data suggest that larger peripheral nerve allografts may not be subject to increased risk for rejection.

Dose-dependent effects of FK506 on neuroregeneration in a rat model.

This study explored the effects of different doses of FK506 on peripheral nerve regeneration, to determine whether neuroregeneration could be enhanced without the toxicity of systemic immunosuppression. In the first part of the study, subimmunosuppressive doses of FK506 were determined by examining skin allograft survival in a rat model. Full-thickness skin grafts (2 cm2) from Wistar rats were grafted to recipient Lewis rats. The procedure was performed for six groups (n = 6). The control group received no FK506, and the other five groups received daily doses of FK506 of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg. Animals that received 2.0 mg/kg FK506 per day exhibited complete skin graft take, whereas all other groups demonstrated complete rejection. After determination of the immunosuppressive dose of FK506, the neuroregenerative effects of different doses of FK506 were explored by assessing nerve regeneration in 80 rats after tibial nerve transection and repair. The control group received no FK506, whereas the other four groups were given daily doses of FK506 of 0.25, 0.5, 1.0, or 2.0 mg/kg. Rats were euthanized at three time points (25, 30, and 35 days), to fully investigate the effects of different FK506 dosing regimens on neuroregeneration. Histomorphometric analyses performed on postoperative days 30 and 35 demonstrated statistically significant improvements in neuroregeneration with subimmunosuppressive FK506 doses of 0.5 and 1.0 mg/kg per day. Therefore, the study demonstrated that neuroregeneration was enhanced at low doses of FK506 that were not sufficient to prevent skin allograft rejection.

Effects of delaying FK506 administration on neuroregeneration in a rodent model.

FK506 is an immunosuppressant drug that has been shown experimentally to stimulate nerve growth and speed functional recovery, when administered immediately after peripheral nerve injury. However, the clinical scenario of a peripheral nerve injury is often associated with either a delayed diagnosis or reconstruction. The purpose of this study was to determine the efficacy of FK506 on neuroregeneration with delayed administration. Thirty-two Lewis rats underwent tibial nerve transection with immediate repair. Animals were left untreated, or were treated with daily injections of FK506 (2 mg/kg), started on the day of surgery, postoperative day 3, or postoperative day 5. Animals underwent walking track analysis to assess functional nerve recovery. Nerves were harvested for histomorphometric analysis on postoperative days 21, 28, and 42. Histomorphometry demonstrated that all treatment groups, regardless of the time of drug initiation, demonstrated evidence of enhanced neuroregeneration, compared to the untreated group. Histomorphometric data from groups harvested on day 21 demonstrated a statistically significant improvement in neuroregeneration in the immediate and 3-day delay groups. Therefore, the beneficial effects of FK506 on neuroregeneration are not restricted to immediate administration, but these effects significantly diminish when FK506 is administered 3 days after nerve injury.

Current approach to radial nerve paralysis.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Identify all potential points of radial nerve compression and other likely causes of radial nerve injury. 2. Accurately diagnose both surgical and nonsurgical causes of radial nerve paralysis. 3. Define a safe and effective approach to the surgical release and reconstruction of the radial nerve. Radial nerve paralysis, which can result from a complex humerus fracture, direct nerve trauma, compressive neuropathies, neuritis, or (rarely) from malignant tumor formation, has been reported throughout the literature, with some controversy regarding its diagnosis and management. The appropriate management of any radial nerve palsy depends primarily on an accurate determination of its cause, severity, duration, and level of involvement. The radial nerve can be injured as proximally as the brachial plexus or as distally as the posterior interosseous or radial sensory nerve. This article reviews the etiology, prognosis, and various treatments available for radial nerve paralysis. It also provides a new classification system and treatment algorithm to assist in the management of patients with radial nerve palsies, and it offers a simple, five-step approach to radial nerve release in the forearm.

The effects of rapamycin in murine peripheral nerve isografts and allografts.

The FKBP-12-binding ligand FK506 has been successfully used to stimulate nerve regeneration and prevent the rejection of peripheral nerve allografts. The immunosuppressant rapamycin, another FKBP-12-binding ligand, stimulates axonal regeneration in vitro, but its influence on nerve regeneration in peripheral nerve isografts or allografts has not been studied. Sixty female inbred BALB/cJ mice were randomized into six tibial nerve transplant groups, including three isograft and three allograft (C57BL/6J) groups. Grafts were left untreated (groups I and II), treated with FK506 (groups III and IV), or treated with rapamycin (groups V and VI). Nerve regeneration was quantified in terms of histomorphometry and functional recovery, and immunosuppression was confirmed with mixed lymphocyte reactivity assays. Animals treated with FK506 and rapamycin were immunosuppressed and demonstrated significantly less immune cell proliferation relative to untreated recipient animals. Although every animal demonstrated some functional recovery during the study, animals receiving an untreated peripheral nerve allograft were slowest to recover. Isografts treated with FK506 but not rapamycin demonstrated significantly increased nerve regeneration. Nerve allografts in animals treated with FK506, and to a lesser extent rapamycin, however, both demonstrated significantly more nerve regeneration and increased nerve fiber widths relative to untreated controls. The authors suggest that rapamycin can facilitate regeneration through peripheral nerve allografts, but it is not a neuroregenerative agent in this in vivo model. Nerve regeneration in FK506-treated peripheral nerve isografts and allografts was superior to that found in rapamycin-treated animals. Rapamycin may have a role in the treatment of peripheral nerve allografts when used in combination with other medications, or in the setting of renal failure that often precludes the use of calcineurin inhibitors such as FK506.