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Introduction/background: Despite inspiring improvements in postamputation pain and prosthetic control, targeted muscle reinnervation (TMR) continues to be underused. With some consistency for recommended nerve transfers developing in the literature, it is necessary to systematize these techniques and simplify their incorporation into routine amputation and neuroma care. This systematic review explores the coaptations reported in the literature to date., Methods: A systematic review of the literature was performed to collect all reports describing nerve transfers in the upper extremity. The preference was directed toward original studies presenting surgical techniques and coaptations used in TMR. All target muscle options were presented for each nerve transfer in the upper extremity., Results: Twenty-one original studies describing TMR nerve transfers throughout the upper extremity met inclusion criteria. A comprehensive list of transfers reported for major peripheral nerves at each upper extremity amputation level was included in tables. Ideal nerve transfers were suggested based on convenience and frequency with which certain coaptations were reported., Conclusions: Increasingly frequent studies are published with convincing outcomes with TMR and numerous options for nerve transfers and target muscles. It is prudent to appraise these options to provide patients with optimal outcomes. Certain muscles are more consistently targeted and can serve as a baseline plan for the reconstructive surgeon interested in incorporating these techniques., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Targeted muscle reinnervation (TMR) outcome studies reveal the benefit amputees experience and the potential functional improvement by optimizing neurocutaneous signaling for myoelectric prosthesis control. However, there are still many settings where these techniques are not offered to patients requiring lower extremity amputations or neuroma reconstruction. With growing consistency in the literature, it is helpful to systematize the nerve transfers described for lower extremity TMR and to simplify its integration into reconstructive care., Methods: A systematic literature review was performed and contained the following inclusion criteria: original cases of primary or secondary lower extremity amputation defects or nerve-related pain that underwent TMR with clearly described target muscles for each nerve transfer. Studies were excluded if the cases had been previously described or contained incomplete data. The primary outcomes were nerves transferred and muscles targeted. Target muscle options were presented in tables specific to anatomic region, and cross-sectional schematics were created for intraoperative assistance., Results: Seventeen studies presenting original cases with clearly described nerve transfers and target muscles in the lower extremity were included in the review. Target muscle selection for all nerve transfers at the transfemoral and transtibial levels were presented in separate tables., Conclusions: Reports of early experience at multiple institutions identify trends in the selection of certain target muscles for nerve transfers in transfemoral and transtibial TMR. Familiarity with these common target muscles and nerve transfers can simplify intraoperative decision-making and enhance integration of lower extremity TMR in amputation care and in the treatment of nerve-related pain., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) of the breast are premalignant lesions. Although the literature on ADH and ALH as a whole is well-developed, research on ADH and ALH incidentally discovered during breast reduction is less robust., Methods: In this study, 355 patients undergoing bilateral reduction mammoplasty at West Virginia University were retrospectively reviewed. A variety of demographic and clinicopathologic variables were collected for each patient, and the incidence of atypical hyperplasia was calculated. Four patients (1.13%) were found to have atypical hyperplasia, three ALH, and one ADH, which is within the range reported in the literature. For patients incidentally found to have atypical hyperplasia, an in-depth analysis of postoperative management was performed., Results: Of the four patients with atypical hyperplasia, three were referred to a cancer center, and one patient followed only with plastic surgery. The three patients who were referred to a cancer center saw a breast surgeon, whereas the patient followed only by plastic surgery did not. None of the four patients received anti-estrogen therapy, but each patient who followed with a cancer center was offered treatment and declined., Conclusions: As a relatively uncommon finding with complex management guidelines, atypical hyperplasia discovered on breast reduction should be referred to a cancer center for long-term follow-up and management when possible. Further research is needed to assess if the management of atypical hyperplasia discovered incidentally after routine reduction should mimic treatment of atypical hyperplasia found after biopsy for suspicion of malignancy., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Introduction: Skin Replacement Technologies (SRTs) emerged as skin alternatives for burns, large excisions or trauma. The original publications represent the available knowledge on a subject and can be modeled as a logistic S-curve which depicts the technology's evolution life-cycle. The Technology Innovation Maturation Evaluation (TIME) model was previously introduced to study the life-cycles of biotechnologies., Methods: PubMed database was searched 1900-2015 to review relevant publications. All skin replacement or regeneration products on the US market were included. The TIME model was applied to assess evolutionary patterns for each technology., Results and Discussion: Three SRT clusters were identified: processed biologics technologies (PBT), extracellular matrix technologies (EMT), and cell-based technologies (CBT). Publications on EMTs and CBTs start decades after PBTs, however, are greater in number and follow an ascending trend. PBTs reached a plateau, suggesting near-senescence. The CBT curve was non-logarithmic and the TIME model could not be applied. The technology initiation point (Ti) for PBTs was 1939 and the establishment point (Te) 1992. For EMT, Ti was 1966 and Te 2010. Sixty-one products were identified (49 EMTs, 7 CBTs, 5 PBTs). PBTs appeared 11 years after Te and EMTs four years prior Te. Thirty-seven products in the EMT category, and one in the PBT category, were developed before Te. The most common FDA regulatory mechanism for SRT was found to be 510(k) followed by HCT/P 361., Conclusion: Innovation is an indicator of the evolution of technology. The number of publications can be used as a metric of this evolution and the fact that the SRT field falls under such pattern demonstrates that SRT is an innovation-based industry. EMT is the most efficient cluster. Few products from SRT registered a commercial success, and from those that did, those technologies were generally found to be part of the most productive cluster, 1st in concept, conceptually simple, easily regulated and produced, cost and clinically efficient, reimbursable, able to solve a specific problem efficiently, had a platform technology design that allowed for further innovation and adaptation for other uses and, as found by application of the TIME model, appear prior to technology establishment., Competing Interests: Dennis P. Orgill is a consultant for Integra® Life Sciences Corp, Mihail Climov is a co-founder of Redact Bio Inc. All other authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: This study investigated the potential of uncultured-stromal-vascular-fraction (SVF) cells in promoting facial nerve regeneration in a rat model., Materials and Methods: A 7-mm nerve defect was created in the buccal branch of facial nerve in five groups of Lewis rats (total n = 30, n = 6 per group). A silicone tube, infused with syngeneic uncultured-SVF was implanted into the facial nerve defect. Groups 1-3 received 1 × 10 3 , 1 × 10 5 , and 1 × 10 7 cells, and regenerated nerves were examined at 13 weeks after the surgery. The findings were compared to the autograft and collagen-alone groups with facial palsy score (FPS), the number of myelinated fibers, fiber diameter, axon diameter, myelin thickness, and g ratio., Results: There was no significant difference in FPS between the autograft and 1 × 10 5 -cell groups at 13 weeks after surgery, and FPS values of these two groups were significantly higher than those of the other three groups (P < 0.01). Axon diameter significantly increased in the 1 × 10 5 -cell group compared with the 1 × 10 3 - (P < 0.05) and 1 × 10 7 -cell groups (P < 0.01). Myelin thickness was found to be the highest in the autograft group, followed by the 1 × 10 5 -, 1 × 10 3 -, 1 × 10 7 -cell, and negative control groups, and there were significant differences among all groups (P < 0.01)., Conclusion: The infusion of uncultured-SVF into the artificial nerve conduit promoted optimal nerve regeneration that was significantly better than nerve conduit alone. © 2016 Wiley Periodicals, Inc. Microsurgery 37:808-818, 2017., (© 2016 Wiley Periodicals, Inc.)

Aldehyde dehydrogenase (ALDH) is an enzyme that plays an important role in retinoid metabolism and highly expressed in stem cells. This study isolated ALDH-expressing cells from subcutaneous adipose tissue and investigated their potential to enhance healing in a full-thickness skin wound in rats by co-implanting them with collagen-glycosaminoglycan (c-GAG) scaffolds. ALDH-positive cells were isolated by a fluorescence-activated cell sorting technique from Lewis rat's stromal-vascular-fraction (SVF) and transplanted with c-GAG scaffolds in a rat full-thickness skin wound model. At 7 days after surgery, the microscopic appearance of c-GAG scaffolds seeded with ALDH-positive was compared with those of uncultured-SVF, and cultured-SVF adipose-derived stromal cells (ASCs). The thickness of cellular ingrowth in the ASC group (630 ± 180 μm) was significantly thicker than that in the control (390 ± 120 μm) or SVF (380 ± 140 μm) groups, but non-significantly thicker than that in the ALDH-positive group (570 ± 220 μm). The thickness of regenerated collagen layer was significantly thicker in the ALDH-positive group (160 ± 110 μm) than in the ASCs (81 ± 41 μm), the control (65 ± 24 μm), or SVF (64 ± 34 μm) groups. Immunofluorescent staining with CD31 proved that transplanted ALDH-positive cells differentiated into vascular endothelial cells in c-GAG scaffolds. Combined transplantation with c-GAG scaffolds and adipose-derived ALDH-positive cells promoted dermal regeneration, giving a possibility that ALDH-positive cells would greatly shorten the waiting period before secondary autologous skin grafting was possible., (© 2016 by the Wound Healing Society.)

Background: Deficiency of autologous skin for reconstruction of severe wounds is a major problem in plastic surgery. Autologous substitutes can provide additional coverage, but due to the duration of production, treatment is significantly delayed. The allogeneic approach offers a potential of having an off-the-shelf solution for the immediate application., Methods: In this study, we assess the engraftment and immunogenicity of allogeneic bilayered bioengineered skin prepared by a self-assembly method. Bioengineered skin has the potential immunological advantage of lacking passenger leukocytes including antigen-presenting cells. The skin constructs were transplanted across major histocompatibility complex (MHC) barriers in a porcine animal model. Animals received a second grafting of the same skin construct 7 weeks after the first set of grafts together with MHC-matched constructs to assess for clinical sensitization., Results: All alloconstructs successfully engrafted with histologic evidence of neovascularization by day 4. Complete cellular rejection and tissue loss occurred by day 8 for most grafts. After the second application, accelerated rejection (<4 days) took place with the development of swine MHC-specific cytotoxic alloantibody., Conclusions: These data demonstrate preclinically that self-assembled allogeneic constructs engraft and reject similar to allogeneic skin despite the absence of professional donor antigen-presenting cells.

Background: Dermal matrices are used to improve healing in both acute and chronic wounds including diabetic and lower extremity wounds, burns, trauma, and surgical reconstruction. The use of dermal matrices for the closure of inflammatory ulcerations is less frequent but growing. Currently available products include decellularized dermis and semisynthetic matrices., Methods: A review of the published literature was performed to identify reports that use acellular dermal matrices in diabetic and inflammatory wounds. Studies were evaluated for quality and outcomes, and a level of evidence was assigned according to the American Society of Plastic Surgeons' Rating Levels of Evidence. Case studies from the authors' experience are also presented., Results: Seventeen primary studies evaluating the use of dermal matrices in diabetic ulcers were identified with 2 based on level I data. There are no prospective clinical trial reports of their use in atypical or inflammatory wounds, but there are several case studies., Conclusions: Treatment of diabetic and inflammatory wounds may include both medical and surgical modalities. The use of dermal matrices can be a useful adjunct, but their optimal use will require future clinical studies.

For patients with extensive burns or donor site scarring, the limited availability of autologous and the inevitable rejection of allogeneic skin drive the need for new alternatives. Existing engineered biologic and synthetic skin analogs serve as temporary coverage until sufficient autologous skin is available. Here we report successful engraftment of a self-assembled bilayered skin construct derived from autologous skin punch biopsies in a porcine model. Dermal fibroblasts were stimulated to produce an extracellular matrix and were then seeded with epidermal progenitor cells to generate an epidermis. Autologous constructs were grafted onto partial- and full-thickness wounds. By gross examination and histology, skin construct vascularization and healing were comparable to autologous skin grafts and were superior to an autologous bilayered living cellular construct fabricated with fibroblasts cast in bovine collagen. This is the first demonstration of spontaneous vascularization and permanent engraftment of a self-assembled bilayered bioengineered skin that could supplement existing methods of reconstruction.

Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity.

Objective: Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV 2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear., Methods: We employed in vivo multiphoton microscopy of the genetically encoded Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo., Results: FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains., Interpretation: Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs., (© 2015 American Neurological Association.)

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.

This paper describes a novel optical method for label-free quantitative imaging of cerebral blood flow (CBF) and intracellular motility (IM) in the rodent cerebral cortex. This method is based on a technique that integrates dynamic light scattering (DLS) and optical coherence tomography (OCT), named DLS-OCT. The technique measures both the axial and transverse velocities of CBF, whereas conventional Doppler OCT measures only the axial one. In addition, the technique produces a three-dimensional map of the diffusion coefficient quantifying nontranslational motions. In the DLS-OCT diffusion map, we observed high-diffusion spots, whose locations highly correspond to neuronal cell bodies and whose diffusion coefficient agreed with that of the motion of intracellular organelles reported in vitro in the literature. Therefore, the present method has enabled, for the first time to our knowledge, label-free imaging of the diffusion-like motion of intracellular organelles in vivo. As an example application, we used the method to monitor CBF and IM during a brief ischemic stroke, where we observed an induced persistent reduction in IM despite the recovery of CBF after stroke. This result supports that the IM measured in this study represent the cellular energy metabolism-related active motion of intracellular organelles rather than free diffusion of intracellular macromolecules.