Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFß pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

Geranylgeraniol (GGOH), incorporated into a bone cement pellet promotes osteoclast function and healing in a model of medication-related osteonecrosis of the jaw.

Introduction: There is no cause -based treatment for Medication-Related Osteonecrosis of the Jaw (MRONJ). MRONJ is a morbid condition including exposed, infected bone and mandibular fractures in osteoporotic individuals and metastatic cancers patients treated with nitrogen containing bisphosphonates (NBP). NBPs inhibit farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, depriving osteoclasts and other bone cells of small GTPases necessary for their function and survival. We test the hypothesis that geranylgeraniol (GGOH),a metabolite downstream of FDPS, when incorporated into a bone cement pellet, enhances osteoclast function and promotes local bone healing in in vitro and in a proven animal model of MRONJ. Methods: 3H labelled GGOH (2 mM) was incorporated into a Hydroset bone cement pellet and release from the cement was assessed over time. To assess the effect on bone cell function, the GGOH-loaded cement was placed in a porous filter above cultured osteoclasts treated with bisphosphonate and the effect on osteoclast survival and function were measured. In a pilot study the effect of GGOH on osteotomy microstructure was measured in a rat model of MRONJ using a split mouth design. Results: The release of GGOH from bone cement increased osteoclast survival/metabolic activity, and promoted resorption of the calcified substrate. In vivo released GGOH limited the effects of the bisphosphonate and promoted healing. In an animal pilot study, GGOH from the infused cement carrier stabilizes bone structure and restores the ability of osteoclasts to remodel. Conclusion: These initial findings point to GGOH in a bone cement carrier as a useful therapeutic approach to prevent or mitigate the pathogenesis of MRONJ.

Evaluating the Healing Potential of J-Plasma Scalpel-Created Surgical Incisions in Porcine and Rat Models.

Cold atmospheric plasma devices generate reactive oxygen and nitrogen species that can be anti-microbial but also promote cell migration, differentiation, and tissue wound healing. This report investigates the healing of surgical incisions created using cold plasma generated by the J-Plasma scalpel (Precise Open handpiece, Apyx Medical, Inc.) compared to a steel scalpel in in vivo porcine and rat models. The J-Plasma scalpel is currently FDA approved for the delivery of helium plasma to cut, coagulate, and ablate soft tissue during surgical procedures. To our knowledge, this device has not been studied in creating surgical incisions but only during deeper dissection and hemostasis. External macroscopic and histologic grading by blinded reviewers revealed no significant difference in wound healing appearance or physiology in incisions created using the plasma scalpel as compared with a steel blade scalpel. Incisions created with the plasma scalpel also had superior hemostasis and a reduction in tissue and blood carryover. Scanning electron microscopy (SEM) and histology showed collagen fibril fusion occurred as the plasma scalpel incised through the tissue, contributing to a sealing effect. In addition, when bacteria were injected into the dermis before incision, the plasma scalpel disrupted the bacterial membrane as visualized in SEM images. External macroscopic and histologic grading by blinded reviewers revealed no significant difference in wound healing appearance or physiology. Based on these results, we propose additional studies to clinically evaluate the use of cold plasma in applications requiring hemostasis or when an increased likelihood of subdermal pathogen leakage could cause surgical site infection (i.e., sites with increased hair follicles).