The Pathophysiology and Management of Pathologic Scarring-a Contemporary Review.

Significance: Pathologic scarring occurs secondary to imbalances in the cellular mechanisms of wound healing and affects millions of people annually. This review article aims to provide a concise overview of the pathophysiology and management of pathologic scarring for clinicians and scientists alike. Recent Advances: Contemporary research in the field has identified aberrations in transforming growth factor-ß/small mothers against decapentaplegic (TGF-ß/SMAD) signaling pathways as key drivers of pathologic scar formation; indeed, this pathway is targeted by many treatment modalities and translational investigations currently underway. Although intralesional injection of corticosteroids has been the gold standard in the treatment of pathologic scarring, studies show greater treatment efficacy with the use of combination injections such as triamcinolone/5-fluorouracil and triamcinolone/botulinum toxin. Adjunctive therapies including ablative fractional carbon dioxide/erbium-doped yttrium aluminum garnet and non-ablative pulsed-dye lasers, microneedling, and carboxytherapy have shown encouraging results in small cohort studies. Translational investigations involving the use of nanogels, RNA interference, and small molecules targeting TGF-ß/SMAD pathways are also currently underway and hold promise for the future. Critical Issues: The heterogeneous nature of hypertrophic scars and keloids poses significant challenges in formulating standardized treatment and assessment protocols, thereby limiting the conclusions that can be drawn. Future Directions: Rigorous clinical trials into the individual and synergistic effects of these therapies would be ideal before any definitive conclusions or evidence-based treatment recommendations can be made. Owing to the heterogeneity of the pathology and patient population, well-conducted cohort studies may be the next best option.

Remote Ischemic Conditioning (RIC) Decreases the Incidence and Severity of Necrotizing Enterocolitis (NEC) - Validation in a Large Animal Model.

BACKGROUND: Necrotizing enterocolitis (NEC) remains a devastating intestinal disease that affects 5-7% of preterm neonates. Remote ischemic conditioning (RIC) has been shown to protect against intestinal ischemia in rodents. We aimed to determine the efficacy of RIC in a large animal model of NEC. METHODS: Using an established piglet model of NEC, preterm piglets of 103-107 days gestation (term = 115 days) were randomly assigned to receive RIC or serve as untreated controls. RIC was initiated at 24 h of life and consisted of 4 cycles of 4-min occlusion followed by reperfusion; cycles were repeated every 24 or 12 h for low frequency (LF) and high frequency (HF) groups, respectively. Piglets were monitored clinically for NEC which was confirmed postmortem using established anatomic and histologic scoring. RESULTS: Eighty-six piglets were randomized into controls (N = 38), LF-RIC (n = 26) and HF-RIC (n = 22) groups. In contrast to the rodent models, in piglets LF-RIC (every 24 h) did not decrease the incidence of NEC compared to controls. However, HF-RIC (every 12 h) significantly reduced the incidence of NEC (OR = 0.13; 95% CI: 0.03, 0.55; p = 0.02) and resulted in a lower severity of NEC (p < 0.0001) compared to controls. CONCLUSIONS: RIC offers protection against NEC in the piglet model only when administered more frequently than in rodents. Further studies are needed to define the optimum frequency of RIC for piglets that may translate to clinical use.

Dysregulation of Nrf2/Keap1 Redox Pathway in Diabetes Affects Multipotency of Stromal Cells.

The molecular and cellular level reaches of the metabolic dysregulations that characterize diabetes are yet to be fully discovered. As mechanisms underlying management of reactive oxygen species (ROS) gain interest as crucial factors in cell integrity, questions arise about the role of redox cues in the regulation and maintenance of bone marrow-derived multipotent stromal cells (BMSCs) that contribute to wound healing, particularly in diabetes. Through comparison of BMSCs from wild-type and diabetic mice, with a known redox and metabolic disorder, we found that the cytoprotective nuclear factor erythroid-related factor 2 (Nrf2)/kelch-like erythroid cell-derived protein 1 (Keap1) pathway is dysregulated and functionally insufficient in diabetic BMSCs (dBMSCs). Nrf2 is basally active, but in chronic ROS, we found irregular inhibition of Nrf2 by Keap1, altered metabolism, and limited BMSC multipotency. Forced upregulation of Nrf2-directed transcription, through knockdown of Keap1, restores redox homeostasis. Normalized Nrf2/Keap1 signaling restores multipotent cell properties in dBMSCs through Sox2 expression. These restored BMSCs can resume their role in regenerative tissue repair and promote healing of diabetic wounds. Knowledge of diabetes and hyperglycemia-induced deficits in BMSC regulation, and strategies to reverse them, offers translational promise. Our study establishes Nrf2/Keap1 as a cytoprotective pathway, as well as a metabolic rheostat, that affects cell maintenance and differentiation switches in BMSCs.

Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing.

Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.