Sensory nerve regeneration and reinnervation in muscle following peripheral nerve injury.

Sensory afferent fibers are an important component of motor nerves and compose the majority of axons in many nerves traditionally thought of as "pure" motor nerves. These sensory afferent fibers innervate special sensory end organs in muscle, including muscle spindles that respond to changes in muscle length and Golgi tendons that detect muscle tension. Both play a major role in proprioception, sensorimotor extremity control feedback, and force regulation. After peripheral nerve injury, there is histological and electrophysiological evidence that sensory afferents can reinnervate muscle, including muscle that was not the nerve's original target. Reinnervation can occur after different nerve injury and muscle models, including muscle graft, crush, and transection injuries, and occurs in a nonspecific manner, allowing for cross-innervation to occur. Evidence of cross-innervation includes the following: muscle spindle and Golgi tendon afferent-receptor mismatch, vagal sensory fiber reinnervation of muscle, and cutaneous afferent reinnervation of muscle spindle or Golgi tendons. There are several notable clinical applications of sensory reinnervation and cross-reinnervation of muscle, including restoration of optimal motor control after peripheral nerve repair, flap sensation, sensory protection of denervated muscle, neuroma treatment and prevention, and facilitation of prosthetic sensorimotor control. This review focuses on sensory nerve regeneration and reinnervation in muscle, and the clinical applications of this phenomena. Understanding the physiology and limitations of sensory nerve regeneration and reinnervation in muscle may ultimately facilitate improvement of its clinical applications.

"Decreasing Postamputation Pain with the Regenerative Peripheral Nerve Interface (RPNI)".

Over 185,000 limb amputations are performed in the United States annually, many of which are due to the sequelae of peripheral vascular disease. Symptomatic neuromas remain a significant source of postamputation morbidity and contribute to both phantom limb (PLP) and residual limb pain (RLP). While many interventions have been proposed for the treatment of symptomatic neuromas, conventional methods lead to a high incidence of neuroma recurrence. Furthermore, these existing methods do not facilitate an ability to properly interface with myoelectric prosthetic devices. The Regenerative Peripheral Nerve Interface (RPNI) was developed to overcome these limitations. The RPNI consists of an autologous free muscle graft secured around the end of a transected nerve. The muscle graft provides regenerating axons with end organs to reinnervate, thereby preventing neuroma formation. We have shown that this simple, reproducible, and safe surgical technique successfully treats and prevents neuroma formation in major limb amputations. In this paper, we describe RPNI surgery in the setting of major limb amputation and highlight the promising results of RPNIs in our animal and clinical studies.

Noninferiority Trial Design: Opportunities and Challenges.

Defining treatment effectiveness is the foundation of evidence-based practice. Most studies comparing the effectiveness of treatment options involve superiority designs in which a treatment is compared against a placebo, standard care, or an alternative treatment. However, in scenarios in which it is not ethical to consider these options, noninferiority designs can be considered. Noninferiority (NI) trials aim to demonstrate that a new treatment is not unacceptably worse than a standard treatment. Noninferiority is determined relative to a noninferiority margin, which is the difference between the test and active control treatment that is not unacceptably clinically inferior. However, there are important considerations with respect to the design, analysis, and interpretation of NI studies, which differ from superiority trials. This review will outline the key components of NI trials, how to interpret the findings, and understand their nuances and potential limitations.

Getting to the Bottom of Patient Experiences with Genital Gender Affirmation Surgery: A Qualitative Analysis of Online Reviews.

BACKGROUND: Patients undergoing gender-affirming surgery seek information from online sources including online reviews written by peers. We aimed to conduct a qualitative analysis of the information discussed in online reviews related to genital gender-affirming surgery and evaluate the topics driving positive/negative reviews. METHODS: Reviews for genital gender-affirming surgery (vaginoplasty, metoidioplasty, and phalloplasty) were identified on three popular review platforms: Google, Yelp, and RealSelf. Content was analyzed line by line using a conventional inductive content analysis to identify recurring themes. Individual statements were marked as either having a positive or negative sentiment. Median rating was calculated and compared across platforms (max score 5). Associations between theme/subthemes and sentiment were also analyzed using Chi-squared test. RESULTS: A total of 129 reviews were analyzed and 433 codes were identified, the majority of which were positive (n=372; 85.9%). Three overarching themes described factors important to patient experience: surgeon medical, surgeon non-medical, and non-surgeon; with surgeon medical being the most popular. Fifteen subthemes comprised these themes, the most popular being interactions with supporting staff, surgeon bedside manner, and overall postoperative result. There was no difference in median review ratings between platforms (5 across all platforms; p=0.452). There was no association between sentiment and themes or subthemes (p=0.187 and p=0.578, respectively). CONCLUSIONS: This study is the first to analyze online reviews of genital gender-affirming surgery. The majority of patients gave positive ratings and the qualitative content had mostly positive sentiment. Salient themes not only include surgeon medical care and outcome, but other nonsurgical elements that formulate the patient's experience as a whole. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Orexinergic modulation of serotonin neurons in the dorsal raphe of a diurnal rodent, Arvicanthis niloticus.

The hypothalamic neuropeptide, orexin (or hypocretin), is implicated in numerous physiology and behavioral functions, including affective states such as depression and anxiety. The underlying mechanisms and neural circuits through which orexin modulates affective responses remain unclear. The objective of the present study was to test the hypothesis that the serotonin (5-HT) system of the dorsal raphe nucleus (DRN) is a downstream target through which orexin potentially manifests its role in affective states. Using a diurnal rodent, the Nile grass rat (Arvicanthis niloticus), we first characterized the expression of the orexin receptors OX1R and OX2R in the DRN using in situ hybridization. The results revealed distinct distributions of OX1R and OX2R mRNAs, with OX1R predominantly expressed in the dorsal and lateral wings of the DRN that are involved in affective processes, while OX2R was mostly found in the ventral DRN that is more involved in sensory-motor function. We next examined how the orexin-OX1R pathway regulates 5-HT in the DRN and some of its projection sites using a selective OX1R antagonist SB-334867 (10 mg/kg, i.p.). A single injection of SB-334867 decreased 5-HT-ir fibers within the anterior cingulate cortex (aCgC); five once-daily administrations of SB-334867 decreased 5-HT-ir not only in the aCgC but also in the DRN, oval bed nucleus of the stria terminalis (ovBNST), nucleus accumbens shell (NAcSh), and periaqueductal gray (PAG). HPLC analysis revealed that five once-daily administrations of SB-334867 did not affect 5-HT turnover to any of the five sites, although it increased the levels of both 5-HT and 5-HIAA in the NAcSh. These results together suggest that orexinergic modulation of DRN 5-HT neurons via OX1Rs may be one pathway through which orexin regulates mood and anxiety, as well as perhaps other neurobiological processes.

Recent Advances in Upper Extremity Microsurgery: From Traditional to Perforator Flaps.

The upper extremity has unique functional and aesthetic requirements. Reconstruction of upper extremity soft tissue defects should ideally provide coverage for vital structures, facilitate early mobilization, be thin and pliable to match its slim contour, and reestablish sensation. Perforator flaps can be raised on the superficial fascia, which creates a thin and pliable yet durable and supple flap option to match the contour and functional needs of the upper extremity. Comparisons to traditional reconstructive methods should be performed to assess whether these innovations in microsurgical reconstruction of upper extremity defects provide an improved functional and aesthetic benefit over traditional methods.

Utilization Trends of Nerve Autograft Alternatives for the Reconstruction of Peripheral Nerve Defects.

BACKGROUND: Autologous nerve grafting is the time-honored reconstruction method for peripheral nerve gaps. However, it is associated with donor-site morbidities. A growing number of studies have demonstrated the effective use of decellularized nerve allograft and synthetic conduits, which are convenient options with no donor deficit. The specific aim of this study was to characterize changes in practice trends for peripheral nerve defect reconstruction. METHODS: The authors queried the 2015 to 2020 Merative MarketScan Databases for patients who underwent nerve autograft, allograft, synthetic conduit, and/or vein graft reconstruction. Patient demographic data (ie, location, indication) and hospital characteristics (ie, facility, provider type) were recorded. Regression analysis identified changes in trends over the study period. RESULTS: A total of 4331 patients underwent one or more nerve gap reconstructive procedures over the study period. Since the introduction of allograft CPT code in 2018, segmented mixed effect longitudinal modeling revealed that allograft utilization significantly increased from 21.5% to 29.6% after 2018 ( P < 0.001), whereas nerve autograft use decreased from 18.6% to 15.8% and conduit use decreased from 60% to 54.7% ( P = 0.09 and P = 0.03, respectively). When stratifying autograft by size, use of autograft less than or equal to 4 cm significantly decreased from 10.6% to 7.7% after 2018 ( P = 0.03), and autograft greater than 4 cm did not. When stratifying by state, there is heterogeneity in utilization rates of each product. CONCLUSION: After creation of a designated allograft CPT code in 2018, there was an increase in allograft use with concomitant decrease in conduit and short length autograft use, suggesting that allograft replaced a portion of procedures used in short nerve gap reconstruction.

Quantifying Nipple-Areolar Complex Shape and Location After Transmasculine Top Surgery: A Study of Postoperative Photographs Posted on Social Media and Surgeons' Professional Websites.

Purpose: The transgender community utilizes online platforms to view and share postoperative masculinizing top surgery photographs. However, the quantitative and qualitative nature of these photographs is unknown. We aimed to conduct an analysis of postoperative online photographs for nipple-areolar complex (NAC) shape and location, and compare social media platforms to World Professional Association for Transgender Health (WPATH) surgeons' websites and published cis-male chest proportions. Methods: In a cross-sectional analysis (April to May 2019), social media (Instagram and Reddit) and WPATH surgeon website postoperative top surgery photographs were analyzed. Areola height (AH):areola width (AW), NAC horizontal (inter-nipple distance [IND]:chest width [CW]) and vertical placement (sternal notch to nipple line [SN-NL]:sternal notch to umbilicus [SN-U]), and vertical scar placement (sternal notch to scar line [SN-SL]:SN-U) ratios were assessed on MATLAB. Data were compared to published cis-male proportions. Photograph skin color, soft tissue redundancy, and scar location were also analyzed. Results: We analyzed 304 social media and 192 surgeons' website photographs qualitatively, and 139 social media and 189 surgeons' photographs quantitatively. Means (standard deviation) for postoperative photographs were AH:AW 1.12±0.24, IND:CW 0.68±0.07, SN-NL:SN-U 0.37±0.06. Most ratios significantly differed from published cis-male ratios (p<0.001). Photographs from WPATH surgeons' websites differed from social media platforms in SN-NL:SN-U and SN-SL:SN-U (p<0.001), and in scar location and soft tissue redundancy (p=0.012). Conclusion: Postoperative top surgery photographs on online platforms showed more vertically oval, caudally positioned, and in many cases wider-spaced NACs than cis-male proportions. Our study highlights variability in results of masculinizing top surgery as it relates to an emerging source of information; online photographs.

Merging Humans and Neuroprosthetics through Regenerative Peripheral Nerve Interfaces.

Limb amputations can be devastating and significantly affect an individual's independence, leading to functional and psychosocial challenges in nearly 2 million people in the United States alone. Over the past decade, robotic devices driven by neural signals such as neuroprostheses have shown great potential to restore the lost function of limbs, allowing amputees to regain movement and sensation. However, current neuroprosthetic interfaces have challenges in both signal quality and long-term stability. To overcome these limitations and work toward creating bionic limbs, the Neuromuscular Laboratory at University of Michigan Plastic Surgery has developed the Regenerative Peripheral Nerve Interface (RPNI). This surgical construct embeds a transected peripheral nerve into a free muscle graft, effectively amplifying small peripheral nerve signals to provide enhanced control signals for a neuroprosthetic limb. Furthermore, the RPNI has the potential to provide sensory feedback to the user and facilitate neuroprosthesis embodiment. This review focuses on the animal studies and clinical trials of the RPNI to recapitulate the promising trajectory toward neurobionics where the boundary between an artificial device and the human body becomes indistinct. This paper also sheds light on the prospects of the improvement and dissemination of the RPNI technology.

The Current State of Fat Grafting in the Hand: A Systematic Review for Hand Diseases.

Autologous fat grafting (AFG) has traditionally been used for facial rejuvenation and soft tissue augmentation, but in recent years, its use has expanded to treat diseases of the hand. Autologous fat grafting is ideal for use in the hand because it is minimally invasive, can restore volume, and has regenerative capabilities. This review summarizes the emerging evidence regarding the safety and efficacy of AFG to the hand in several conditions, including systemic sclerosis, Dupuytren disease, osteoarthritis, burns, and traumatic fingertip injuries. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature search on the use of AFG in hand pathologies was performed on October 8, 2020, in Ovid MEDLINE, Elsevier Embase, Clarivate Web of Science, and Wiley Cochrane Central Register of Controlled Trials. The retrieved hits were screened and reviewed by 2 independent reviewers and a third reviewer adjudicated when required. Reviewers identified 919 unique hits. Screening of the abstracts identified 22 manuscripts which described the use of AFG to treat an identified hand condition. Studies suggest AFG in the hands is a safe, noninvasive option for the management of systemic sclerosis, Dupuytren contracture, osteoarthritis, burns, and traumatic fingertip injuries. While AFG is a promising therapeutic option for autoimmune, inflammatory, and fibrotic disease manifestations in the hand, further studies are warranted to understand its efficacy and to establish more robust clinical guidelines. Studies to date show the regenerative, immunomodulatory, and volume-filling properties of AFG that facilitate wound healing and restoration of hand function with limited complications.

Dermal Sensory Regenerative Peripheral Nerve Interface for Reestablishing Sensory Nerve Feedback in Peripheral Afferents in the Rat.

BACKGROUND: Without meaningful, intuitive sensory feedback, even the most advanced myoelectric devices require significant cognitive demand to control. The dermal sensory regenerative peripheral nerve interface (DS-RPNI) is a biological interface designed to establish high-fidelity sensory feedback from prosthetic limbs. METHODS: DS-RPNIs were constructed in rats by securing fascicles of residual sensory peripheral nerves into autologous dermal grafts, with the objectives of confirming regeneration of sensory afferents within DS-RPNIs and establishing the reliability of afferent neural response generation with either mechanical or electrical stimulation. RESULTS: Two months after implantation, DS-RPNIs were healthy and displayed well-vascularized dermis with organized axonal collaterals throughout and no evidence of neuroma. Electrophysiologic signals were recorded proximal from DS-RPNI's sural nerve in response to both mechanical and electrical stimuli and compared with (1) full-thickness skin, (2) deepithelialized skin, and (3) transected sural nerves without DS-RPNI. Mechanical indentation of DS-RPNIs evoked compound sensory nerve action potentials (CSNAPs) that were like those evoked during indentation of full-thickness skin. CSNAP firing rates and waveform amplitudes increased in a graded fashion with increased mechanical indentation. Electrical stimuli delivered to DS-RPNIs reliably elicited CSNAPs at low current thresholds, and CSNAPs gradually increased in amplitude with increasing stimulation current. CONCLUSIONS: These findings suggest that afferent nerve fibers successfully reinnervate DS-RPNIs, and that graded stimuli applied to DS-RPNIs produce proximal sensory afferent responses similar to those evoked from normal skin. This confirmation of graded afferent signal transduction through DS-RPNI neural interfaces validate DS-RPNI's potential role of facilitating sensation in human-machine interfacing. CLINICAL RELEVANCE STATEMENT: The DS-RPNI is a novel biotic-abiotic neural interface that allows for transduction of sensory stimuli into neural signals. It is expected to advance the restoration of natural sensation and development of sensorimotor control in prosthetics.

Extended Abdominal Pedicled Flap Using a Modified Abdominoplasty Incision for Reconstruction of an Extensive Forearm Defect.

Extensive upper extremity traumatic defects are challenging to reconstruct. Regional flaps are often too small or have pedicles in the zone of injury. Free microvascular flaps are not ideal options in the presence of extensive vascular injuries and in patients who cannot tolerate long procedures. We present a case featuring an extended abdominal flap using abdominoplasty-like incisions that facilitated simultaneous abdominoplasty and soft tissue coverage of an extensive, traumatic defect of the forearm and hand in a patient who was not a candidate for free flap.

Fat Grafting Subjectively Improves Facial Skin Elasticity and Hand Function of Scleroderma Patients.

Systemic scleroderma is a chronic connective tissue disease characterized by internal organ and skin fibrosis. Unfortunately, there is a lack of efficacious treatments for cutaneous manifestations, and alternative interventions should be considered. Fat grafting has gained significant attention due to its regenerative properties and success in improving skin quality and volume deficits in fibrotic diseases. While some studies have investigated the efficacy of autologous fat grafting, we utilized the Coleman method for harvesting and processing to determine the efficacy of fat grafting to improve skin fibrosis in the hands and face of scleroderma patients without excess processing of adipose tissue. Patients with a diagnosis of scleroderma who underwent fat grafting between March 2015 and March 2019 at the University of Michigan were included. Ten female patients were identified that met inclusion criteria. The mean age at the time of surgery was 48.7 (± 17.6) years. An average of 53.2 (± 15.5) ml of fat was injected into the hands and 26.1 (± 16.4) ml into the face. Patients were treated with 1-4 rounds of grafting depending on the initial severity of skin fibrosis and volume deficiency. Fat grafting subjectively and qualitatively improved perioral skin quality, facial animation, hand range of motion, and hand pain for patients with systemic scleroderma. No complications were identified. Additional studies are necessary to determine the ideal volume, timing of treatments, and type of fat to optimize the efficacy of autologous fat grafting for the treatment of systemic scleroderma.

Evolution of Cranioorbital Shape in Nonsyndromic, Muenke, and Saethre-Chotzen Bilateral Coronal Synostosis: A Case-Control Study of 2-Year Outcomes.

BACKGROUND: The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up. METHODS: Volumetric, linear, and angular analyses were performed on computed tomographic scans of consecutive bilateral coronal synostosis patients. Comparisons were made across three time points, between syndromic and nonsyndromic cases, and against normal controls. Significance was set at p < 0.05. RESULTS: Twenty-five patients were included: 11 were nonsyndromic, eight had Saethre-Chotzen syndrome, and six had Muenke syndrome. Total cranial volume was comparable to normal, age-matched control subjects before and 2 years after surgery despite an expansion during surgery. Axial and sagittal vector analyses showed advancement and widening of the lower forehead beyond control values with surgery and comparable anterior position, but increased width compared to controls at 2 years. Frontal bossing decreased with a drop in anterior cranial height and advanced lower forehead position. Middle vault height was not normalized and turricephaly persisted at follow-up. Posterior fossa volume remained lower at all three time points compared to control subjects. Supraorbital retrusion relative to anterior corneal position was overcorrected by surgery, with values comparable to those of control subjects at 2 years because of differential growth. There was no difference at 2 years between syndromic and nonsyndromic groups. CONCLUSIONS: Open fronto-orbital advancement successfully remodels the anterior forehead but requires overcorrection to be comparable to normal at 2 years. Although there are differences in syndromic cases at presentation, they do not result in significant morphometric differences on follow-up. Posterior fossa volume remains lower at all time points. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Shoulder Release and Tendon Transfer following Neonatal Brachial Plexus Palsy: Gains, Losses, and Midline Function.

BACKGROUND: Shoulder release and tendon transfer is frequently performed to address persistent weakness from neonatal brachial plexus palsy. Although postoperative improvements in motion are well described, associated deficits are poorly documented, and functional assessments are lacking. Loss of ability to reach midline can occur with surgery and may result in impairment. The purpose of this study was to comprehensively assess the gains, losses, functional changes, and patient-reported outcome associated with the authors' surgical approach. METHODS: Consecutive patients undergoing surgery with 2-year follow-up were included (n = 30). Prospectively recorded assessments by therapists were reviewed. Changes were assessed by t test and Wilcoxon rank sum (p < 0.05). RESULTS: Active external rotation and abduction improved and internal rotation diminished. Aggregate modified Mallet score increased with improvements in all subscales, except that hand to spine was unchanged and hand to belly decreased. Functional assessment using the Brachial Plexus Outcome Measure revealed an increase of aggregate score, with no decline in any subscales. Improvements were in hand to back of head, forward overhead reach, holds plate with palm up, opening large container, and strings bead. Aggregate patient self-report of appearance and function increased (from 18 to 23). Loss of ability to reach midline occurred in three patients (10 percent) who had extended Erb or total palsy and preoperative limitations of internal rotation. CONCLUSIONS: Secondary reconstruction rebalances shoulder motion by increasing external rotation and abduction and reducing internal rotation. In this study, a conservative surgical approach results in overall improvement in task-based abilities and self-reported outcomes and preservation of internal rotation within a functional range. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker.

PURPOSE: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. EXPERIMENTAL DESIGN: Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. RESULTS: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. CONCLUSIONS: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.

Practical Computed Tomography Scan Findings for Distinguishing Metopic Craniosynostosis from Metopic Ridging.

BACKGROUND: Premature fusion of the metopic suture (ie, metopic craniosynostosis) can be difficult to discriminate from physiological closure of the metopic suture with ridging (MR). Yet, MCS is treated surgically, whereas MR is treated nonsurgically. Often, the diagnosis can be made by physical examination alone, but in difficult cases, a computed tomography (CT) scan can add additional diagnostic information. METHODS: We de-identified, randomized, and analyzed the CT scans of patients with MCS (n = 52), MR (n = 20) and age-matched normative controls (n = 52) to identify specific findings helpful in distinguishing between MCS and MR. Four expert clinicians were blinded to the clinical diagnosis and assessed each CT for features of the orbits, frontal bones, and inner table of calvaria. RESULTS: Although no single feature was diagnostic of MCS, we identified several signs that were correlated with MCS, MR, or controls. Features such as "posteriorly displaced frontal bone" and "frontal bone tangent to mid-orbit or medial" demonstrated higher correlation with MCS than MR and the addition of other features improves the accuracy of diagnosis as did inclusion of the interfrontal divergence angle. CONCLUSION: The presence of a closed metopic suture in addition to other CT scan findings may improve the accuracy of diagnosing MCS, MR, and normocephaly.