Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal ...excisional wounds in circadian clock neuronal PAS domain 2 (
)-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates
activity. The hit compound (Dwn1) suppressed circadian
expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgfβ1, and α-smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.
Abstract Recently bone graft substitutes using bone morphogenetic proteins (BMPs) have been heralded as potential alternatives to traditional bone reconstruction procedures. BMP-based products, ...however, are associated with significant and potentially life-threatening side effects when used in the head and neck region and furthermore, are exorbitantly priced. Oxysterols, products of cholesterol oxidation, represent a class of molecules that are favorable alternatives or adjuncts to BMP therapy due to their low side effect profile and cost. In order to establish the optimal clinical utility of oxysterol, an optimal scaffold must be developed, one that allows the release of oxysterol in a sustained and efficient manner. In this study, we prepare a clinically applicable bone graft substitute engineered for the optimal release of oxysterol. We first solubilized oxysterol in water by making use of polymeric micelles using l -lactic acid oligomer (LAo) grafted gelatin. Then, the water-solubilized oxysterol was incorporated into a biodegradable hydrogel that was enzymatically degraded intracorporeally. In this manner, oxysterol could be released from the hydrogel in a degradation-driven manner. The water-solubilized oxysterol incorporated biodegradable hydrogel was implanted into rat calvarial defects and induced successful bone regeneration. The innovative significance of this study lies in the development of a bone graft substitute that couples the osteogenic activity of oxysterol with a scaffold designed for optimized oxysterol release kinetics, all of which lead to better repair of bone defects.
Abstract Background Negative pressure wound therapy (NPWT) is a widely accepted method of temporary coverage for complex lower extremity wounds before definitive reconstruction. However, the precise ...role of NPWT in the perioperative management of patients with complicated lower extremity injuries remains unclear. In this study, we examine the effect of NPWT on flap complications and overall outcomes based on timing of soft-tissue reconstruction relative to initial injury and implementation of NPWT. Methods We retrospectively reviewed the medical records of 32 consecutive patients presenting to a single institution receiving lower extremity reconstruction after Gustilo class IIIB or IIIC open tibial fractures over a 5-y period. Length of hospitalization, number of surgical procedures, flap failure, infection, and nonunion were parameters of interest in this study. Results The incidence of complications in patients treated with NPWT was lower compared with patients who underwent wet-to-dry dressing changes, regardless of when surgery was performed. The highest rate of complications was observed in patients operated on >6 wk after injury and who received wet-to-dry dressing changes wound care. By comparison, those who underwent surgery within 1 wk of injury and who were bridged with NPWT had the lowest rate of complications. Conclusions The use of NPWT therapy in the perioperative management of patients with open lower extremity fractures reduces complication rates associated with limb salvage surgery. Our results suggest that NPWT can be used as a temporizing measure to optimize patients before flap surgery, effectively lengthening the window of opportunity for definitive reconstruction.
The core circadian gene Neuronal PAS domain 2 (
) is expressed in dermal fibroblasts and has been shown to play a critical role in regulating collagen synthesis during wound healing. We have ...performed high throughput drug screening to identify genes responsible for downregulation of
while maintaining cell viability. From this, five FDA-approved hit compounds were shown to suppress
expression in fibroblasts. In this study, we hypothesize that the therapeutic suppression of
by hit compounds will have two effects: (1) attenuated excessive collagen deposition and (2) accelerated dermal wound healing without hypertrophic scarring.
To test the effects of each hit compound (named Dwn1, 2, 3, 4, and 5), primary adult human dermal fibroblasts (HDFa) were treated with either 0, 0.1, 1, or 10 μM of a single hit compound. HDFa behaviors were assessed by picrosirius red staining and quantitative RT-PCR for
collagen synthesis, cell viability assay,
fibroblast-to-myofibroblast differentiation test, and cell migration assays.
Dwn1 and Dwn2 were found to significantly affect collagen synthesis and cell migration without any cytotoxicity. Dwn3, Dwn4, and Dwn5 did not affect collagen synthesis and were thereby eliminated from further consideration for their role in mitigation of gene expression or myofibroblast differentiation. Dwn1 also attenuated myofibroblast differentiation on HDFa.
Dwn1 and Dwn2 may serve as possible therapeutic agents for future studies related to skin wound healing.
Unilateral diaphragmatic paralysis causes respiratory deficits and can occur after iatrogenic or traumatic phrenic nerve injury in the neck or chest. Patients are evaluated using spirometry and ...imaging studies; however, phrenic nerve conduction studies and electromyography are not widely available or considered; thus, the degree of dysfunction is often unknown. Treatment has been limited to diaphragmatic plication. Phrenic nerve operations to restore diaphragmatic function may broaden therapeutic options.
An interventional study of 92 patients with symptomatic diaphragmatic paralysis assigned 68 (based on their clinical condition) to phrenic nerve surgical intervention (PS), 24 to nonsurgical (NS) care, and evaluated a third group of 68 patients (derived from literature review) treated with diaphragmatic plication (DP). Variables for assessment included spirometry, the Short-Form 36-Item survey, electrodiagnostics, and complications.
In the PS group, there was an average 13% improvement in forced expiratory volume in 1 second (p < 0.0001) and 14% improvement in forced vital capacity (p < 0.0001), and there was corresponding 17% (p < 0.0001) and 16% (p < 0.0001) improvement in the DP cohort. In the PS and DP groups, the average postoperative values were 71% for forced expiratory volume in 1 second and 73% for forced vital capacity. The PS group demonstrated an average 28% (p < 0.01) improvement in Short-Form 36-Item survey reporting. Electrodiagnostic testing in the PS group revealed a mean 69% (p < 0.05) improvement in conduction latency and a 37% (p < 0.0001) increase in motor amplitude. In the NS group, there was no significant change in Short-Form 36-Item survey or spirometry values.
Phrenic nerve operations for functional restoration of the paralyzed diaphragm should be part of the standard treatment algorithm in the management of symptomatic patients with this condition. Assessment of neuromuscular dysfunction can aid in determining the most effective therapy.
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