Cell therapy - showing cells the way home

The clinical potential of cell-based therapies is limited by poor targeting of systemically infused cells to diseased tissues. In our recent study, we have developed a multi-step screening platform to identify small molecules that boost the homing properties of mesenchymal stem cells (MSCs) to sites of inflammation. First, a medium-throughput screen was designed to identify small molecules that upregulate surface expression of the homing integrin, cd11a (integrin αL). Ro-31-8425, a kinase inhibitor, was identified as the most potent inducer of cd11a surface expression, and was also shown to significantly increase MSC firm adhesion to the endothelial ligand of cd11a, ICAM-1, using a microfluidics-based firm adhesion assay. Finally, systemically infused Ro-31-8425-pretreated MSCs displayed improved homing to sites of inflammation and a superior anti-inflammatory impact in a murine ear inflammation model

QS2: Outcomes Of Pediatric Dynamic Facial Reanimation After Two Decades

Purpose: Pediatric facial paralysis has substantial functional consequences in a growing child including impaired quality of life. Microneurovascular facial reanimation is the gold standard for smile reconstruction; however, quantitative data are lacking regarding long-term outcomes, particularly beyond 10 years. The primary objective of this study was to evaluate the long-term surgical and patient-reported outcomes after dynamic reconstruction of unilateral facial paralysis in childhood. Methods: A cross-sectional study was performed of patients in our institutional facial paralysis database (1978-2008) who underwent dynamic reconstruction of unilateral facial paralysis 20 or more years ago. All patients were treated as children with a staged cross face nerve graft and free functioning muscle transfer. Frontal facial photographs in repose and maximal smile prior to surgery, within 2 years post-surgery, and at long term follow-up were analyzed using the MEEI Face-Gram software for commissure excursion. Patient-reported outcomes were obtained using the FaCE Scale for subjective facial impairment and disability, as well as the FACE-Q Satisfaction with Outcome and FACE-Q Social Function scales. Results are reported as median [IQR] and non-parametric statistical analysis was performed with alpha of 0.05. Results: Eleven patients were included with long term follow-up of 23.7 [5.6] years (6 females, 5 males; 5 congenital, 6 acquired; age at surgery 7.3 [6.3] years). For surgical quantitative measures, commissure excursion significantly improved from prior to surgery (-1.3 [7.4] mm) compared to follow up within 2 years post-surgery (7.0 [1.7] mm) (p0.05). For patient-reported outcomes, median FaCE Scale scores showed good function for social function (81/100), oral function (88/100), facial comfort (92/100), and overall score (75/100). On the FACE-Q Satisfaction with Outcome scale, 10/11 respondents somewhat agreed or definitely agreed with the statement, “I am pleased with the result.” On the FACE-Q Social Function scale, 10/11 respondents somewhat agreed or definitely agreed with the statements, “I make a good first impression” and “I feel confident when I participate in group situations.” Conclusion: Dynamic reconstruction of unilateral facial paralysis in young children improves commissure excursion that is maintained at long-term follow up. As adults, these patients report a high level of satisfaction and social functioning with their smile reconstruction

Dynamic Reconstruction of Facial Paralysis in Craniofacial Microsomia

BACKGROUND: Craniofacial microsomia is associated with maxillomandibular hypoplasia, microtia, soft-tissue deficiency, and variable severity of cranial nerve dysfunction, most often of the facial nerve. This study evaluated the incidence of facial paralysis in patients with craniofacial microsomia and outcomes after free functioning muscle transfer for dynamic smile reconstruction. METHODS: A single-center, retrospective, cross-sectional study was performed from 1985 to 2018 to identify pediatric patients with craniofacial microsomia and severe facial nerve dysfunction who underwent dynamic smile reconstruction with free functioning muscle transfer. Preoperative and postoperative facial symmetry and oral commissure excursion during maximal smile were measured using photogrammetric facial analysis software. RESULTS: This study included 186 patients with craniofacial microsomia; 41 patients (21 male patients, 20 female patients) had documented facial nerve dysfunction (22 percent) affecting all branches (51 percent) or the mandibular branch only (24 percent). Patients with severe facial paralysis (n = 8) underwent smile reconstruction with a free functioning muscle transfer neurotized either with a cross-face nerve graft (n = 7) or with the ipsilateral motor nerve to masseter (n =1). All patients achieved volitional muscle contraction with improvement in lip symmetry and oral commissure excursion (median, 8 mm; interquartile range, 3 to 10 mm). The timing of orthognathic surgery and facial paralysis reconstruction was an important consideration in optimizing patient outcomes. CONCLUSIONS: The authors' institution's incidence of facial nerve dysfunction in children with craniofacial microsomia is 22 percent. Free functioning muscle transfer is a reliable option for smile reconstruction in children with craniofacial microsomia. To optimize outcomes, a novel treatment algorithm is proposed for craniofacial microsomia patients likely to require both orthognathic surgery and facial paralysis reconstruction

Management of congenital melanocytic nevi in the plastic surgery clinic: Families′ expectations and their persistent concern about malignancy

BACKGROUND Children with congenital melanocytic nevi (CMN) were historically managed with surgical removal to lower the risk of malignant transformation. The evolving literature over the last decade has indicated a significantly lower risk than previously estimated. Indications for excision currently revolve around aesthetic and psychosocial concerns. This study describes and evaluates the perspectives and expectations of patients and families referred to a pediatric plastic surgery clinic on CMN management. METHOD A two-part questionnaire was administered before and after an initial clinic appointment to evaluate patient and family concerns of lesion growth, risk of malignancy, treatment expectations, and stigmatization. RESULTS Thirty questionnaires were completed for 11 male and 19 female patients, mean age 9.2 years (1-25). Referring doctors (majority dermatologists) were rarely concerned about malignancy (8%), but parents listed it as a top reason for wanting the CMN removed (37%) and the most common expectation for the visit followed by information about surgical options and outcome. Before the clinic, 93% were at least "slightly" worried about CMN growth and 96% about malignancy, whereas 63% and 72%, respectively, after the clinic. CONCLUSIONS Families want information about surgical excision and are concerned about malignancy, indicating lingering misinformation or misconception about melanoma risk. For the majority, CMN removal remains at least slightly important, presumably for aesthetic reasons and remaining concern about malignancy. Involved health care professionals should assure reliable and coherent patient information about MM risk, indications for surgery and expected outcome to best support families' decision-making

Management of congenital melanocytic nevi in the plastic surgery clinic: Families' expectations and their persistent concern about malignancy

BACKGROUND Children with congenital melanocytic nevi (CMN) were historically managed with surgical removal to lower the risk of malignant transformation. The evolving literature over the last decade has indicated a significantly lower risk than previously estimated. Indications for excision currently revolve around aesthetic and psychosocial concerns. This study describes and evaluates the perspectives and expectations of patients and families referred to a pediatric plastic surgery clinic on CMN management. METHOD A two-part questionnaire was administered before and after an initial clinic appointment to evaluate patient and family concerns of lesion growth, risk of malignancy, treatment expectations, and stigmatization. RESULTS Thirty questionnaires were completed for 11 male and 19 female patients, mean age 9.2 years (1-25). Referring doctors (majority dermatologists) were rarely concerned about malignancy (8%), but parents listed it as a top reason for wanting the CMN removed (37%) and the most common expectation for the visit followed by information about surgical options and outcome. Before the clinic, 93% were at least "slightly" worried about CMN growth and 96% about malignancy, whereas 63% and 72%, respectively, after the clinic. CONCLUSIONS Families want information about surgical excision and are concerned about malignancy, indicating lingering misinformation or misconception about melanoma risk. For the majority, CMN removal remains at least slightly important, presumably for aesthetic reasons and remaining concern about malignancy. Involved health care professionals should assure reliable and coherent patient information about MM risk, indications for surgery and expected outcome to best support families' decision-making

A cell-based drug delivery platform for treating central nervous system inflammation

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases.National Institutes of Health (Grant HL095722