Molecular Basis of Surgical Coaptation Techniques in Peripheral Nerve Injuries.

Peripheral nerve injuries requiring surgical repair affect over 100,000 individuals in the US annually. Three accepted methods of peripheral repair include end-to-end, end-to-side, and side-to-side neurorrhaphy, each with its own set of indications. While it remains important to understand the specific circumstances in which each method is employed, a deeper understanding of the molecular mechanisms underlying the repair can add to the surgeon's decision-making algorithm when considering each technique, as well as help decide nuances in technique such as the need for making epineurial versus perineurial windows, length and dept of the nerve window, and distance from target muscle. In addition, a thorough knowledge of individual factors that are active in a particular repair can help guide research into adjunct therapies. This paper serves to summarize the similarities and divergences of the three commonly used nerve repair strategies and the scope of molecular mechanisms and signal transduction pathways in nerve regeneration as well as to identify the gaps in knowledge that should be addressed if we are to improve clinical outcomes in our patients.

Sensorimotor Outcomes of Upper Extremity End-to-Side Nerve Transfers: A Meta-analysis.

BACKGROUND: End-to-side nerve transfer (ETSNT) for treatment of peripheral nerve injuries is controversial given the myriad anatomic locations, injury types, and indications. Efficacy of ETSNT remains debated. We hypothesized differences in age, sex, transfer location, and time to surgery influence outcomes. METHODS: We performed a search of the PubMed database for ETSNT in the upper extremity from 1988 to 2018. Age, sex, transfer location, time to surgery, donor and recipient axons, and strength and sensation outcomes as measured by Medical Research Council scale were extracted from articles. Meaningful recovery was classified as Medical Research Council Grade 3 or greater. Association between meaningful recovery and younger (<25) and older (≥25) patients, injury mechanism, sex, transfer location, donor axons, and recipient axons were calculated using a χ 2 or Fisher exact test. A logistic mixed effect model was used with time to surgery, age (categorical), transfer location, and injury type as a fixed effect, and a random paper effect was included to account for correlation among patients from the same paper. RESULTS: One hundred fifteen patients from 11 studies were included. Neither age (continuous variable, P = 0.68) nor time to surgery ( P = 0.28) affected meaningful recovery. Injury mechanism, sex, and younger age (<25 vs ≥25 years) were not associated with meaningful recovery. Within the brachial plexus ETSNT demonstrated median M4 ± 1 postoperative strength, with trunks/cords as the primary axon donor ( P = 0.03). The musculocutaneous nerve demonstrated promising but variable results in 31 patients with median strength M3 ± 4. Digital nerves consistently demonstrated meaningful sensory recovery as both donor and recipient axons (15 of 15, 100%). Logistic regression analysis demonstrated that odds of meaningful recovery after ETSNT are significantly greater for transfers within the brachial plexus compared with the distal arm (odds ratio, 41.9; 95% CI, 1.1-1586.7, P = 0.04), but location does not significantly affect meaningful recovery ( P = 0.22). CONCLUSIONS: Patients undergoing ETSNT for digital nerve injury demonstrated meaningful recovery. End-to-side nerve transfer seems to be more efficacious when performed within the brachial plexus. This study did not find sex, injury mechanism, or time to surgery to significantly affect meaningful recovery. Additional study is needed to better evaluate the effectiveness of ETSNT in the upper extremity.

Substance Addiction and the Hand Surgery Patient: A Comprehensive Review.

Substance abuse is pervasive in the American society, with 10% of the United States population using marijuana, up to 17% of patients undergoing upper-extremity surgery reporting chronic opioid use, and up to 20% of acute hand infections occurring secondary to intravenous drug use. It is common, therefore, for a hand surgeon to take care of a patient under the influence of nonprescription drugs. The range of abused substances is diverse, and the implications are profound. As such, it is important for hand surgeons to understand the potential implications of drug use to best guide patient care and surgical decision-making. The abuse of opioids, amphetamines, marijuana, and other substances has an impact on treatment timing, adherence to postoperative hand therapy, and/or clinic follow ups. The physiologic effects of these drugs affect surgical risk, wound healing, and bone healing. Social factors associated with drug abuse can complicate the management of these patients. Collectively, all these factors substantially affect surgical outcomes. In this review, we provide an overview of commonly abused illicit and prescription drugs seen in hand surgery practice, tips to identify substance abuse, the drugs' implications for surgical risks, outcomes, and some recommendations for management.

Optimizing Collagen Scaffolds for Bone Engineering: Effects of Cross-linking and Mineral Content on Structural Contraction and Osteogenesis.

INTRODUCTION: Osseous defects of the craniofacial skeleton occur frequently in congenital, posttraumatic, and postoncologic deformities. The field of scaffold-based bone engineering emerged to address the limitations of using autologous bone for reconstruction of such circumstances. In this work, the authors evaluate 2 modifications of three-dimensional collagen-glycosaminoglycan scaffolds in an effort to optimize structural integrity and osteogenic induction. METHODS: Human mesenchymal stem cells (hMSCs) were cultured in osteogenic media on nonmineralized collagen-glycosaminoglycan (C-GAG) and nanoparticulate mineralized collagen-glycosaminoglycan (MC-GAG) type I scaffolds, in the absence and presence of cross-linking. At 1, 7, and 14 days, mRNA expression was analyzed using quantitative real-time -reverse-transcriptase polymerase chain reaction for osteocalcin (OCN) and bone sialoprotein (BSP). Structural contraction was measured by the ability of the scaffolds to maintain their original dimensions. Mineralization was detected by microcomputed tomographic (micro-CT) imaging at 8 weeks. Statistical analyses were performed with Student t-test. RESULTS: Nanoparticulate mineralization of collagen-glycosaminoglycan scaffolds increased expression of both OCN and BSP. Cross-linking of both C-GAG and MC-GAG resulted in decreased osteogenic gene expression; however, structural contraction was significantly decreased after cross-linking. Human mesenchymal stem cells-directed mineralization, detected by micro-CT, was increased in nanoparticulate mineralized scaffolds, although the density of mineralization was decreased in the presence of cross-linking. CONCLUSIONS: Optimization of scaffold material is an essential component of moving toward clinically translatable engineered bone. Our current study demonstrates that the combination of nanoparticulate mineralization and chemical cross-linking of C-GAG scaffolds generates a highly osteogenic and structurally stable scaffold.

Computed tomography image guidance for more accurate repair of anterior table frontal sinus fractures.

BACKGROUND: Anterior table frontal sinus fractures accompanied by nasofrontal duct injury require surgical correction. Extracranial approaches for anterior table osteotomies have traditionally used plain radiograph templates or a "cut-as-you-go" technique. We compared these methods with a newer technique utilizing computed tomography (CT)-guided imaging. METHODS: Data of patients with acute, traumatic anterior table frontal sinus fractures and nasofrontal duct injury between 2009 and 2013 were reviewed (n = 29). Treatment groups compared were as follows: (1) CT image guidance, (2) plain radiograph template, and (3) cut-as-you-go. Frontal sinus obliteration was performed in all cases. Demographics, operative times, length of stay, complications, and osteotomy accuracy were recorded. RESULTS: Similar demographics, concomitant injuries, operative times, and length of stay among groups were noted. No patients in the CT-guided group had perioperative complications including intraoperative injury of the dura, cerebrum, or orbital structures. In the plain radiograph template group, 25% of patients had inadvertent dural exposure, and 12.5% required take-back to the operating room for cranial bone graft donor site hematoma. In the cut-as-you-go group, 11% required hardware removal for exposure. There were no cases of cerebrospinal fluid leak, meningitis, or mucocele in any group (follow-up, 29.2 months). The CT image guidance group had the most accuracy of the osteotomies (95%) compared with plain radiograph template (85%) and the cut-as-you-go group (72.5%). CONCLUSIONS: A new technique using CT image guidance for traumatic frontal sinus fractures repair offers more accurate osteotomy and elevation of the anterior table without increased operative times or untoward sequelae.

Mohs versus surgical excision in nonmelanoma skin cancers: does location matter?

INTRODUCTION: Every year, nearly 1.2 million people are affected by nonmelanoma skin cancers (NMSCs) in the United States. Most published data focus on comparing the efficacy of Mohs micrographic surgery (MMS) versus traditional surgical excision (TSE) for NMSCs in H-zone lesions of the face. There is paucity of data regarding the 2 treatments in other areas such as the non-H-zone areas of the face, the trunk, and extremities. Our study focused on the efficacy of the 2 treatments in areas of the body where the skin was not of premium. METHOD: A retrospective chart review was performed of patients with NMSCs treated with TSE at the West Los Angeles Veterans Affairs Hospital between 2000 and 2008. Patients with at least a 3-year follow-up were selected for the study. Institutional review board approval was obtained before commencement of the study. Age, sex, and race-matched patients were selected in the MMS group. Data collected included demographic data, tumor characteristics, surgical treatment, reconstructions, recurrence rates, complications, and follow-up course. Data were analyzed using SigmaStat 3.5. RESULTS: A total of 588 patients were treated for NMSCs at our institute between 2000 and 2008, of which 289 patients had non-H-zone, extremity, and trunk lesions. The follow-up period for these patients was at least 3 years. Average age of this group was 67.1 (11.4) with 89.9% being males. Age, sex, and race-matched group of 200 patients treated with MMS for NMSCs were randomly chosen from the same time range. Average size of lesions was 17.4 (16.9) mm in the TSE group and 1.1 (0.4) mm in the MMS group (P < 0.05). Primary reconstruction was performed in non-premium areas (ie, non-H-zone areas of the face, the trunk, and extremities) in 98.7% patients in the TSE group and 61.5% patients in the MMS group (P < 0.05). Secondary reconstructive rate was 1.3% in TSE compared to 37.5% in MMS. Overall recurrence rate was 4.8% (compared to 3% with MMS). Of the 29 patients who had recurrences within the TSE group, 27 were H-zone lesions and 2 were non-H-zone lesions. DISCUSSION: One of the primary goals of NMSC management is to treat the lesion with adequate oncologic margins, while preserving maximal function and cosmesis. Our data look at the non-premium areas to quantify the clinical efficacy of TSE versus MMS. The size of lesions treated by TSE was significantly larger than those treated by MMS in all areas of the body. The primary closure rates were significantly higher and secondary procedure rates significantly lower in the TSE group compared to the MMS group, in non-premium areas. Our data suggest that patients with NMSCs may be more effectively treated with TSE than MMS in non-premium areas of the body. Additional studies are ongoing, including economic modeling and cost analysis.

In vitro mineralization of human mesenchymal stem cells on three-dimensional type I collagen versus PLGA scaffolds: a comparative analysis.

BACKGROUND: Development of a tissue engineered bone graft requires efficient bioactivity screening of biomaterials in clinically relevant three-dimensional systems. The authors analyzed the relative osteogenic potential of two three-dimensional biomaterials--type I collagen and poly(L-lactide-co-glycolide) (PLGA)--to support in vitro mineralization of human mesenchymal stem cells. METHODS: Human mesenchymal stem cells were seeded onto three-dimensional PLGA or type I collagen scaffolds; incubated in osteogenic media; and harvested at 1, 4, and 7 days. Messenger RNA expression was analyzed using quantitative real-time reverse-transcriptase polymerase chain reaction for osteogenic (i.e., alkaline phosphatase, osteocalcin, bone sialoprotein, Runx2/core binding factor α-1) and angiogenic (i.e., vascular endothelial growth factor and interleukin-8) markers. Alkaline phosphatase enzyme activity was measured at 4 and 7 days. Mineralization was detected by alizarin red staining and micro-computed tomographic imaging at 8 and 12 weeks. Mineral composition was analyzed by solid-phase nuclear magnetic resonance spectroscopy. RESULTS: Early osteogenic and angiogenic markers, and alkaline phosphatase enzyme activity, were up-regulated on PLGA versus collagen scaffolds. However, long-term mineralization endpoints favored type I collagen. By 8 weeks, human mesenchymal stem cells on collagen exhibited significantly higher mineral density by micro-computed tomographic and alizarin red staining than PLGA scaffolds. Both biomaterials deposited calcium hydroxyapatite as determined by nuclear magnetic resonance spectroscopy. CONCLUSIONS: The authors' findings suggest that despite early PLGA induction of osteogenic gene expression, long-term mineralization occurs earlier and to a greater extent on type I collagen, highlighting collagen as a potential bone tissue engineering scaffold in the human mesenchymal stem cell niche. When screening the relative osteoinductive profiles of three-dimensional bone tissue engineering scaffolds in vitro, the authors recommend including long-term endpoints of osteogenesis.

Human and mouse osteoprogenitor cells exhibit distinct patterns of osteogenesis in three-dimensional tissue engineering scaffolds.

BACKGROUND: Understanding interspecies variation between animal models and humans is essential to develop tissue-engineered bone. The authors studied osteogenic and angiogenic marker expression in human and murine osteoblasts and mesenchymal stem cells. METHODS: Three human cells (human mesenchymal stem cells, multilineage progenitor cells, and normal human osteoblasts) and three murine cells (MC3T3-E1, C3H10T1/2, and M2-10B4) were used. Cells were seeded onto poly-lactide-glycolic acid-coated tissue culture plates or three-dimensional poly-lactide-glycolic acid scaffolds, incubated in osteogenic medium, and harvested at 1, 4, and 7 days. mRNA expression was analyzed using quantitative real-time reverse-transcriptase polymerase chain reaction for osteogenic markers, including alkaline phosphatase, osteocalcin, bone sialoprotein, and core-binding factor alpha-1, and angiogenic markers, including vascular endothelial growth factor and interleukin-8. Data were analyzed using analysis of variance. RESULTS: All human cells had significantly increased expression of osteogenic markers in three dimensions compared with two dimensions (alkaline phosphatase by 220 percent, osteocalcin by 323 percent, bone sialoprotein by 534 percent, and core-binding factor alpha-1 by 357 percent). However, all murine cells exhibited significant decreases in the expression of osteogenic markers in three-dimensional compared with two-dimensional cultures (alkaline phosphatase by 89 percent, osteocalcin by 64 percent, bone sialoprotein by 76 percent, and core-binding factor alpha-1 by 73 percent). In contrast, all human and murine cells showed markedly elevated expression of angiogenic factors interleukin-8 and vascular endothelial growth factor in three-dimensional compared with two-dimensional cultures. Measurement of alkaline phosphatase activity confirmed this pattern of osteogenic differentiation. CONCLUSIONS: In three-dimensional versus two-dimensional cultures, osteogenesis increased significantly in human cells but decreased in murine cells; angiogenesis increased regardless of species. Since three-dimensional cultures represent in vivo conditions more closely, this species variation has important translational implications to tissue-engineered bone research.

Sex differences in the long-term outcome after a severe thermal injury.

We have recently shown that during the acute phase, postburn female pediatric burn patients had significantly increased levels of anabolic hormones with an associated decreased hypermetabolism leading to a significant shorter intensive care unit stay compared with male patients. The aim of the present study was to determine possible differences between girls and boys in body composition, hypermetabolism, and hormone pattern in the long term. Sixty-two children (1-16 years old) who sustained a severe thermal injury (>or=40% total body surface area) were included into the study. Patients were further divided into girls (n = 22) and boys (n = 40). Patient demographics, nutritional support, and mortality were noted. Resting energy expenditure (REE) was measured by indirect calorimetry, body composition by dual-energy x-ray absorptiometry (Hologic Inc, Waltham, Mass) at discharge, 3, 6, 9, 12, 18, and 24 months after burn. In addition, blood was drawn at the same time points, and serum hormones were measured. There were no significant differences between girls and boys for demographics, nutritional intake, or concomitant injuries. Predicted REE was significantly decreased in girls at discharge, 6, 12, and 18 months postburn (P < 0.05). Dual-energy x-ray absorptiometry scan showed that girls had improved change in bone mineral content and percent fat compared with boys (P < 0.05). There were no differences in changes in height, body weight, lean body mass, and total fat between groups. Girls had significantly higher levels of insulinlike growth factor 1, insulinlike growth factor binding protein 3, free thyroxine index, T4, and insulin when compared with boys (P < 0.05). No differences were found for T3 uptake, osteocalcin, cortisol, growth hormone, and parathyroid hormone (PTH) between groups. Data indicate that girls have a reduced REE associated with changes in bone content and endogenous anabolic hormones.

Liposomal gene transfer of keratinocyte growth factor improves wound healing by altering growth factor and collagen expression.

BACKGROUND: Growth factors affect the complex cascade of wound healing; however, interaction between different growth factors during dermal and epidermal regeneration are still not entirely defined. In the present study, we thought to determine the interaction between keratinocyte growth factor (KGF) administered as liposomal cDNA with other dermal and epidermal growth factors and collagen synthesis in an acute wound. MATERIALS AND METHODS: Rats received an acute wound and were divided into two groups to receive weekly subcutaneous injections of liposomes plus the Lac-Z gene (0.22 microg, vehicle), or liposomes plus the KGF cDNA (2.2 microg) and Lac-Z gene (0.22 microg). Histological and immunohistochemical techniques were used to determine growth factor, collagen expression, and dermal and epidermal structure. RESULTS: KGF cDNA increased insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), and fibroblast growth factor (FGF), decreased transforming growth factor-beta (TGF-beta), while it had no effect on platelet-derived growth factor (PDGF) levels in the wound. KGF cDNA significantly increased collagen Type IV at both the wound edge as well as the wound bed, while it had no effect on collagen Type I and III. KGF cDNA increased re-epithelialization, improved dermal regeneration, and increased neovascularization. CONCLUSIONS: Exogenous administered KGF cDNA causes increases in IGF-I, IGF-BP3, FGF, and collagen IV and decreases TGF-beta concentration. KGF gene transfer accelerates wound healing without causing an increase in collagen I or III.

Blood transfusions are associated with increased risk for development of sepsis in severely burned pediatric patients.

OBJECTIVE: To determine the risk of developing sepsis following transfusion of blood products in severely burned pediatric patients. DESIGN: Retrospective, cohort study. SETTING: Shriners Hospital for Children and University Hospital. PATIENTS: Severely burned pediatric patients with >30% total body surface area (TBSA) burn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy-seven pediatric burn patients over a period of 7 yrs (1997-2004) were included in the study, with 25 patients being septic at admission and therefore excluded. Patients were stratified according to TBSA burn and presence or absence of inhalation injury. The amounts of packed red blood cells (RBCs) and fresh frozen plasma (FFP) were recorded during hospital stay before the development of sepsis. Blood product administration was normalized for the number of surgeries and divided into two groups: high (RBCs>20/FFP>5) or low (RBCs<20/FFP<5) amount of blood products. Sepsis was diagnosed based on the criteria set by the Society of Critical Care Medicine in conjunction with positive blood culture or presence of organisms in the organs at autopsy. By stratifying the groups into low and high blood transfusion, we found that patients with >60% TBSA burn with inhalation injury have an 8% risk of developing sepsis in the low RBC group, which increases to 58% in the high RBC group (p<.05). Similar results were found for RBCs per operation, FFP, and FFP per operation (p<.05). There were no differences in age and gender between groups. CONCLUSIONS: Pediatric burn suffering from a 60% TBSA burn with concomitant inhalation injury are more likely to develop sepsis if they are given high amounts of blood products, indicating an immunocompromised state following blood transfusion.

Cytokine expression profile over time in severely burned pediatric patients.

A severe burn leads to hypermetabolism and catabolism resulting in compromised function and structure of essential organs. The massive release of cytokines is implicated in this hypermetabolic response. The aim of the present study was to compare cytokine expression profiles from severely burned children without signs of infections or inhalation injury (n = 19) to the cytokine profiles from normal, noninfected, nonburned children (n = 14). The Bio-Plex suspension array system was used to measure the concentration of 17 cytokines. The expression of proinflammatory and anti-inflammatory cytokines was maximal during the first week after thermal injury. Significant increases were measured for 15 mediators during the first week after thermal injury: interleukin (IL) 1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p70, IL-13, IL-17, interferon gamma, monocyte chemoattractant protein 1, macrophage inflammatory protein 1beta, and granulocyte colony-stimulating factor (P < 0.05). Granulocyte-macrophage colony-stimulating factor was significantly increased during the second week after burn (P < 0.05). Within 5 weeks, the serum concentrations of most cytokines decreased, approaching normal levels. When compared with the cytokine levels measured in normal children, a total of 16 cytokines were significantly altered (P < 0.05). After severe burn, a specific cytokine expression profile is observed in patients without complications such as inhalation injury or sepsis. The cytokine concentrations decrease during 5 weeks after burn but remain elevated over nonburned values. Furthermore, the elevation in most serum cytokine levels during the first week after burn may indicate a potential window of opportunity for therapeutic intervention.

The pharmacologic modulation of the hypermetabolic response to burns.

Patients with burns less than 40% TBSA do not have catabolism unless sepsis develops. Those with burns more than 40% TBSA always experience catabolism, which causes metabolic derangements that persist for at least 1 year after the injury in most body tissues. The accomplishments of the past decade have placed us in the midst of an exciting paradigm shift from what used to be a primary concern (ie, mortality) to areas that are more likely to enhance the quality of life of burn survivors. Modulating postburn hypermetabolism for the burned patient is of overwhelming importance in both the immediate care stage and the rehabilitative stage. Postburn hypermetabolism cannot be completely reversed but may be manipulated by nonpharmacologic and pharmacologic means. Early burn wound excision and complete wound closure, prevention of sepsis, the maintenance of thermal neutrality for the patient by elevation of the ambient temperature, and graded resistance exercises during convalescence are simple, highly effective primary treatment goals. Although the initial burn injury and sepsis-related complications principally determine the extent of the metabolic response in burn victims, obligatory activity, background- and procedural-related pain, and anxiety also greatly increase metabolic rates. Judicious maximal narcotic support, appropriate sedation, and supportive psychotherapy are mandatory if their effects are to be minimized. Several anabolic and anticatabolic agents are available for use during immediate care and rehabilitation. Exogenous, continuous low-dose insulin infusion, beta-blockade with propranolol, and the use of the synthetic testosterone analogue oxandrolone are the most cost-effective and least toxic therapies to date. These greatly assist therapeutic minimization of the loss of lean body mass and linear growth delay and are effective in burned patients with and without sepsis. Adverse effects, cost benefits, and the ease of administration and monitoring must be examined when considering the possibility of their use.