Minimally invasive scar release by autologous adipose tissue transfer for post-traumatic neuropathic pain.

Introduction: Addressing post traumatic lower limb neuropathic pain is challenging across medical specialties. To address this potentially devastating condition, several invasive and non-invasive approaches have been proposed with inconsistent results. Adipose fat transfer (AFT), also known as fat grafting, is a regenerative medicine technique in which a patient's own fat is harvested from one area of the body (usually through liposuction) and then injected into another area for various purposes, such as aesthetic contour enhancement or reconstruction and regeneration of scarred tissues. Methods: We analyze the effects of fat grafting for neuropathic pain combined with neuroma excision (hybrid technique, hAFT) or alone (AFT). A retrospective review was conducted on 22 patients with neuropathic lower limb pain, after trauma or orthopedic surgery treated with hAFT (n = 9) or AFT (n = 13). Results: Reduction in VAS scale more than 50 % was observed in 6 patients (66 %) treated with hybrid technique and in eleven patients (85 %) treated with AFT alone. Among these, complete pain reduction (>91 %) was achieved in 33.3 % of hAFT and 54 % of AFT technique. A 3.2 points reduction in VAS was found in the hAFT group versus 5.8 points in the AFT group (p = 0.035). Conclusion: This pioneering use of AFT emerges as a minimally invasive breakthrough, promising significant improvement in reconstructing scarred subcutaneous tissue and managing neuropathic pain.

Minimally invasive nerve and artery sparing surgical approach for temporal migraines.

Background: Temporal migraines (TM) present with throbbing, pulsating headaches in the temporal area. Different surgical techniques ranging from resecting the auriculotemporal nerve (ATN) and or ligating the superficial temporal artery (STA) have shown similar good results to decrease TM symptoms. No conclusive data supports a specific disease of the STA in TM patients. A minimally invasive technique is proposed to preserve both vascular and nerve structures. Methods: Patients with drug resistant TM were selected and treated with two techniques: nerve sparing and nerve and artery sparing. The study included 57 patients with TM, with an average age of 47.5 years. TM improvement was quantified after at least one year of follow up time. STA biopsies were sent for histological analysis. Results: Forty-two patients underwent nerve-sparing decompression, with a therapeutic success rate of 78.6%, corresponding to 22.1 days with migraine per month decreasing to 6.2. Histological analysis of the STA showed varying degrees of endofibrosis in 75% of the samples. Histological results do not correlate with the intensity of symptoms before or after surgery. Fifteen patients underwent nerve and artery sparing arteriolysis, with an overall therapeutic success rate of 86.6% of which 80% had >90% improvement. The average migraine days dropped from 24 to 2.5 days per month in this group. Conclusion: Minimally invasive nerve sparing approaches are an effective and safe treatment to improve drug resistant TM symptoms. Endofibrosis of the STA was present in 75% of the cases, but it was found to be unrelated to pre-operative symptoms and outcome. Results are promising, but the limited numbers of patients treated with artery and nerve sparing technique needs further investigations.

Minimally Invasive Nerve- and Muscle-Sparing Surgical Decompression for Occipital Neuralgia.

BACKGROUND: Occipital neuralgia is a well-defined type of headache, and its treatment algorithm is still debated across medical specialties. From the analysis of the literature, it appears that surgical decompression of the occipital nerves is the most effective invasive approach to improve the quality of life of patients with occipital neuralgia refractory to medications. The authors describe here a minimally invasive nerve- and muscle-sparing technique to decompress the occipital nerves. METHODS: The results in terms of reduction of migraine days per month, use of medications, pain evaluation, and decrease in Migraine Headache Index were analyzed by means of a retrospective chart review of 87 patients who underwent nerve- and muscle-sparing surgical decompression of the greater and lesser monolateral or bilateral occipital nerves in their institution and were followed up for at least 12 months. The surgical technique is described in detail. RESULTS: Surgical decompression significantly reduced occipital neuralgia burden (at least 50% improvement) in 91% of patients, with 45% reporting a complete remission of occipital pain. Days with pain per month decreased by 80%, chronic background pain intensity decreased by 81%, and pain intensity during crisis decreased by 76%. Accordingly, drug use dropped by approximately 70%. Only minor complications were reported in four patients. CONCLUSIONS: The described technique could contribute to and further support surgical decompression as the first option among the invasive approaches to treat occipital neuralgia. Results corroborate previous findings, adding a less-invasive, nerve- and muscle-sparing approach. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Portable bioluminescent platform for in vivo monitoring of biological processes in non-transgenic animals.

Bioluminescent imaging (BLI) is one of the most powerful and widely used preclinical imaging modalities. However, the current technology relies on the use of transgenic luciferase-expressing cells and animals and therefore can only be applied to a limited number of existing animal models of human disease. Here, we report the development of a "portable bioluminescent" (PBL) technology that overcomes most of the major limitations of traditional BLI. We demonstrate that the PBL method is capable of noninvasive measuring the activity of both extracellular (e.g., dipeptidyl peptidase 4) and intracellular (e.g., cytochrome P450) enzymes in vivo in non-luciferase-expressing mice. Moreover, we successfully utilize PBL technology in dogs and human cadaver, paving the way for the translation of functional BLI to the noninvasive quantification of biological processes in large animals. The PBL methodology can be easily adapted for the noninvasive monitoring of a plethora of diseases across multiple species.

Selective denervation of the corrugator supercilii muscle for the treatment of idiopatic trigeminal neuralgia purely paroxysmal distributed in the supraorbital and suprathrochlear dermatomes.

INTRODUCTION: Idiopatic trigeminal neuralgia purely paroxysmal (ITNp) distributed in the supraorbital and suprathrochlear dermatomes (SSd), refractory to conventional treatments have been linked to the hyperactivity of the corrugator supercilii muscle (CSM). In these patients, the inactivation of the CSM via botulinum toxin type A (BTA) injections has been proven to be safe and effective in reducing migraine burden. The main limitation of BTA is the need of repetitive injections and relative high costs. Based on the study of the motor innervation of the CSM, we describe here an alternative approach to improve these type of migraines, based on a minimally invasive denervation of the CSM. MATERIALS AND METHODS: Motor innervation and feasibility of selective CSM denervation was first studied on fresh frozen cadavers. Once the technique was safely established, 15 patients were enrolled. To be considered eligible, patients had to meet the following criteria: positive response to BTA treatment, migraine disability assessment score > 24, > 15 migraine days/month, no occipital/temporal trigger points and plausible reasons to discontinue BTA treatment. Pre- and post- operative migraine headache index (MHI) were compared, and complications were classified following the Clavien-Dindo classification (CDC). RESULTS: Fifteen patients (9 females and 6 males) underwent the described surgical procedure. The mean age was 41 ± 10 years. Migraine headache episodes decreased from 24 ± 4 day/month to 2 ± 2 (p < 0.001) The MHI decreased from 208 ± 35 to 10 ± 11 (p < 0.001). One patient (7%) had a grade I complication according to the CDC. No patient needed a second operative procedure. CONCLUSIONS: Our findings suggest that the selective CSM denervation represents a safe and minimally invasive approach to improve ITNp distributed in the SSd associated with CSM hyperactivation. TRIAL REGISTRATION: The data collection was conducted as a retrospective quality assessment study and all procedures were performed in accordance with the ethical standards of the national research committee and the 1964 Helsinki Declaration and its later amendments.

Chronic Knee and Ankle Pain Treatment through Selective Microsurgical Approaches: A Minimally Invasive Option in the Treatment Algorithm for Refractory Lower Limb Pain.

BACKGROUND: Injury or compression of a sensory nerve is an under-reported source of disabling pain in the lower limb. It is known that peripheral nerve microsurgeons can reconstruct and rewire injured nerves to relieve chronic pain but this option remains not completely understood and ignored by most orthopaedic surgeons, neurologists, and pain therapists. In this paper, we describe our experience with knee and ankle peripheral nerve surgery to improve the condition of patients suffering from chronic, posttraumatic lower limb pain. PATIENTS AND METHODS: Between 2015 and 2018, a retrospective investigation was performed including patients who underwent ankle and knee nerve surgery for posttraumatic chronic pain with at least 1 year of follow-up. Previous surgeries or type of trauma, pain location and characteristics, type of operation (reconstruction, decompression, or denervation), and number of nerves operated were listed. Selective neuropathy was confirmed by ultrasound-guided nerve blocks. Outcome was assessed combining the visual analogue scale (VAS) score at rest and during movement, functional indexes, drug use, and ability to work. RESULTS: A total of 34 patients (14 knee and 20 ankle) were included in this study. A statistically significant difference (p < 0.05%) in postoperative pain at rest and during activity was seen in both groups of patients. Good to excellent outcomes were recorded in 92 and 80% of patients treated, respectively, at the knee and the ankle levels. No major complications occurred, while a secondary procedure due to neuroma recurrence was necessary in seven patients (three knees and four ankles). CONCLUSION: Peripheral nerve microsurgery is a useful and minimally invasive tool to be added in the algorithm of treatment of chronic knee and ankle pain. Physicians should be trained to suspect a neuropathic origin of pain in absence of musculoskeletal signs of pathology, especially following trauma or surgeries.

Embryonic stem cell extracts improve wound healing in diabetic mice.

AIMS/HYPOTHESIS: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.

The Greater Occipital Nerve and Obliquus Capitis Inferior Muscle: Anatomical Interactions and Implications for Occipital Pain Syndromes.

BACKGROUND: The compression/injury of the greater occipital nerve has been identified as a trigger of occipital headaches. Several compression points have been described, but the morphology of the myofascial unit between the greater occipital nerve and the obliquus capitis inferior muscle has not been studied yet. METHODS: Twenty fresh cadaveric heads were dissected, and the greater occipital nerve was tracked from its emergence to its passage around the obliquus capitis inferior. The intersection point between the greater occipital nerve and the obliquus capitis inferior, and the length and thickness of the obliquus capitis inferior, were measured. In addition, the nature of the interaction and whether the nerve passed through the muscle were also noted. RESULTS: All nerves passed either around the muscle loosely (type I), incorporated in the dense superficial muscle fascia (type II), or directly through a myofascial sleeve within the muscle (type III). The obliquus capitis inferior length was 5.60 ± 0.46 cm. The intersection point between the obliquus capitis inferior and the greater occipital nerve was 6.80 ± 0.68 cm caudal to the occiput and 3.56 ± 0.36 cm lateral to the midline. The thickness of the muscle at its intersection with the greater occipital nerve was 1.20 ± 0.25 cm. Loose, tight, and intramuscular connections were found in seven, 31, and two specimens, respectively. CONCLUSIONS: The obliquus capitis inferior remains relatively immobile during traumatic events, like whiplash injuries, placing strain as a tethering point on the greater occipital nerve. Better understanding of the anatomical relationship between the greater occipital nerve and the obliquus capitis inferior can be clinically useful in cases of posttraumatic occipital headaches for diagnostic and operative planning purposes.

Double Triangular Cartilage Excision Otoplasty.

BACKGROUND: Prominent ears have a negative impact on patients' psychosocial well-being. There are numerous surgical correction techniques described, but the majority have high complication and recurrence rates. In this article, the authors present a stitchless technique that takes advantage of different approaches to minimize complications and recurrences. METHODS: The authors prospectively studied patients who underwent a bilateral double triangular cartilage excision otoplasty in an outpatient setting. This prominent ear setback technique is based on a specific cartilage excision to mechanically collapse the ear without using any sutures through the cartilage. Postoperatively, surgical complications were classified according to the Clavien-Dindo classification. The patient-reported outcome was analyzed after completion of a questionnaire 6 months after surgery, and another clinical follow-up appointment was arranged 12 months after surgery. RESULTS: Sixty patients (120 ears) with an average age of 24 years were studied, and the overall complication rate was 6 percent. Three ears (2.5 percent) developed superficial cutaneous necrosis at the anterior concha, and one ear (1 percent) required an additional correction for unsatisfactory pinna rotation. Also, 2.5 percent of the patients experienced a grade I complication, and 1 percent of the patients experienced a grade IIIa complication according to the Clavien-Dindo classification. No wound infections, hematomas, or hypertrophic scars were observed, and the patient-reported outcome showed satisfaction with the results. CONCLUSIONS: The authors' findings show that the double triangular cartilage excision otoplasty is a safe procedure with low complication/recurrence rates. This stitchless technique should be included in each surgeon's repertoire as an alternative to previously published surgical techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Minimal Undermining Suspension Technique (MUST): Combined Eyebrow and Mid-face Lift via Temporal Access.

BACKGROUND: Less downtime following esthetic interventions leads to the popularity of injectable solutions for facial rejuvenation treatments. Surgical interventions for esthetic purposes are usually associated with higher complication rates and longer recovery times when compared to less invasive treatments. Here we present for the first time a minimally invasive surgical technique for a simultaneous mid-face and eyebrow lift using one small temporal incision. MATERIALS AND METHODS: We prospectively studied patients who underwent facial rejuvenation using a minimal undermining suspension technique (MUST) in an outpatient setting. Postoperatively, surgical complications were classified according to the Clavien-Dindo classification. Preoperatively and at 12-month post-intervention, patient-reported outcomes were described using the FACE-Q questionnaire. Pre- and postoperative pictures were compared using MERZ Aesthetic Scales. RESULTS: Fifty-five patients (50 females and 5 males) with a mean age of 47 years were studied. The overall complication rate was 19%, whereas 18 patients (15%) developed an ecchymosis of the orbicular temporal region and two patients (4%) developed a dimple caused by the anchor of the suture. No displacements of the palpebral rim or injuries to the facial nerve were observed. Recovery time was in average 7 days and no long-term complications were seen. Both, the FACE-Q and the MERZ Aesthetic Scales showed significant improvements at 12-month post-surgery (p < 0.01). CONCLUSIONS: The MUST can be used as a minimal invasive procedure for facial rejuvenation with a short downtime and low complication rate. The discreet temporal access and the MUST dissector allowed a safe dissection of anatomical tissue planes to perform safely a mid-face and eyebrow lift. Further studies are warranted to prove long-term outcomes. LEVEL OF EVIDENCE IV: 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 A3 online Instructions to Authors. www.springer.com/00266 .

Anatomic and Compression Topography of the Lesser Occipital Nerve.

BACKGROUND: The surgical treatment of occipital headaches focuses on the greater, lesser, and third occipital nerves. The lesser occipital nerve (LON) is usually transected with relatively limited available information regarding the compression topography thereof and how such knowledge may impact surgical treatment. METHODS: Eight fresh frozen cadavers were dissected focusing on the LON in relation to 3 clinically relevant compression zones. The x axis was a line drawn through the occipital protuberance (OP) and the y axis, the posterior midline (PM). In addition, a prospectively collected cohort of 36 patients who underwent decompression of the LON is presented with their clinical results, including migraine headache index scores. RESULTS: The LON was found in compression zone 1, with a mean of 7.8 cm caudal to the OP and 6.3 cm lateral to the PM. The LON was found at the midpoint of compression zone 2, with an average of 5.5 cm caudal to the OP and 6.2 cm lateral to the PM. At compression zone 3, the medial-most LON branch was located approximately 1 cm caudal to the OP and 5.35 cm lateral to the PM, whereas the lateral-most branch was identified 1 cm caudal to the OP and 6.5 cm lateral to the PM. Of the 36 decompression patients analyzed, only 5 (14%) required neurectomy as the remainder achieved statistically significant improvements in migraine headache index scores postoperatively. CONCLUSION: The knowledge of LON anatomy can aid in nerve dissection and preservation, thereby leading to successful outcomes without requiring neurectomy.

The Outcome of Primary Subglandular Breast Augmentation Using Tumescent Local Anesthesia.

BACKGROUND: Tumescent local anesthesia (TLA) technique to obtain regional anesthesia and vasoconstriction of the skin and subcutaneous tissues is routinely adopted for several plastic surgery procedures. Here, we describe the use of TLA in primary subglandular breast augmentation. This series evaluates advantages and disadvantages of TLA in elective augmentation breast surgery as well as patients' response to this procedure. METHODS: Between December 2008 and November 2011, 150 patients underwent bilateral primary subglandular breast augmentation under TLA and conscious sedation in the presence of a board-certified anesthesiologist. Midazolam 0.05 mg/kg IV and ranitidine 100 mg IV were given as premedication. Tumescent local anesthesia was composed of 25 mL of lidocaine 2%, 8 mEq of sodium bicarbonate, and 1 mL of epinephrine (1 mg/1 mL) in 1000 mL of 0.9% NS. The solution was delivered between the pectoral fascia and the mammary gland via a spinal needle. After infiltration, 45 minutes were allowed before surgery for local anesthetic effects to take place. RESULTS: The mean age of the patients was 34.3 years. The average amount of tumescent solution infiltrated was 1150 mL, with a maximal dose of 17 mg/kg of lidocaine used. Operating time was 45 minutes and recovery room time averaged 125 minutes. Minor complications were found in a total of 9 (5.3%) patients, with no main surgery-related complications such as hematoma or seroma formation. CONCLUSIONS: Breast augmentation under TLA and conscious sedation proved to be safe in the presence of a board-certified anesthesiologist and when performed with meticulous surgical technique.

Novel micropatterns mechanically control fibrotic reactions at the surface of silicone implants.

Over the past decade, various implantable devices have been developed to treat diseases that were previously difficult to manage such diabetes, chronic pain, and neurodegenerative disorders. However, translation of these novel technologies into clinical practice is often difficult because fibrotic encapsulation and/or rejection impairs device function after body implantation. Ideally, cells of the host tissue should perceive the surface of the implant being similar to the normal extracellular matrix. Here, we developed an innovative approach to provide implant surfaces with adhesive protein micropatterns. The patterns were designed to promote adhesion of fibroblasts and macrophages by simultaneously suppressing fibrogenic activation of both cell types. In a rat model, subcutaneously implanted silicone pads provided with the novel micropatterns caused 6-fold lower formation of inflammatory giant cells compared with clinical grade, uncoated, or collagen-coated silicone implants. We further show that micropatterning of implants resulted in 2-3-fold reduced numbers of pro-fibrotic myofibroblast by inhibiting their mechanical activation. Our novel approach allows controlled cell attachment to implant surfaces, representing a critical advance for enhanced biointegration of implantable medical devices.

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice.

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

Foam pore size is a critical interface parameter of suction-based wound healing devices.

BACKGROUND: Suction-based wound healing devices with open-pore foam interfaces are widely used to treat complex tissue defects. The impact of changes in physicochemical parameters of the wound interfaces has not been investigated. METHODS: Full-thickness wounds in diabetic mice were treated with occlusive dressing or a suction device with a polyurethane foam interface varying in mean pore size diameter. Wound surface deformation on day 2 was measured on fixed tissues. Histologic cross-sections were analyzed for granulation tissue thickness (hematoxylin and eosin), myofibroblast density (α-smooth muscle actin), blood vessel density (platelet endothelial cell adhesion molecule-1), and cell proliferation (Ki67) on day 7. RESULTS: Polyurethane foam-induced wound surface deformation increased with polyurethane foam pore diameter: 15 percent (small pore size), 60 percent (medium pore size), and 150 percent (large pore size). The extent of wound strain correlated with granulation tissue thickness that increased 1.7-fold in small pore size foam-treated wounds, 2.5-fold in medium pore size foam-treated wounds, and 4.9-fold in large pore size foam-treated wounds (p < 0.05) compared with wounds treated with an occlusive dressing. All polyurethane foams increased the number of myofibroblasts over occlusive dressing, with maximal presence in large pore size foam-treated wounds compared with all other groups (p < 0.05). CONCLUSIONS: The pore size of the interface material of suction devices has a significant impact on the wound healing response. Larger pores increased wound surface strain, tissue growth, and transformation of contractile cells. Modification of the pore size is a powerful approach for meeting biological needs of specific wounds.

Nonactivated versus thrombin-activated platelets on wound healing and fibroblast-to-myofibroblast differentiation in vivo and in vitro.

BACKGROUND: Platelet preparations for tissue healing are usually preactivated before application to deliver concentrated growth factors. In this study, the authors investigated the differences between nonactivated and thrombin-activated platelets in wound healing. METHODS: The healing effects (i.e., wound closure, myofibroblast formation, and angiogenesis) of nonactivated and thrombin-activated platelets were compared in experimental wounds in diabetic (db/db) animals. In vitro, fibroblast phenotype and function were tested in response to platelets and activated platelets. No treatment served as a negative control. RESULTS: Wounds treated with platelets reached 90 percent closure after 15 days, faster than activated platelets (26 days), and with higher levels of myofibroblasts and angiogenesis. In vitro, platelets enhanced cell migration and induced two-fold higher myofibroblast differentiation and contraction compared with activated platelets. CONCLUSIONS: Platelets stimulate wound healing more efficiently compared with activated platelets by enhancing fibroblast differentiation and contractile function. Similar levels of growth factors may induce different biological effects when delivered "on demand" rather than in an initial bolus.

A review of the role of mechanical forces in cutaneous wound healing.

Cutaneous wound healing is a complex process with many types of mechanical forces regulating the quality and speed of healing. The role of mechanical forces in regulating tissue growth, repair and remodelling was recognised more than a century ago. Such forces influence gene expression, the synthesis of growth factors and inflammatory mediators and cellular processes like proliferation of many load-sensitive cells. However, the exact mechanisms by which these forces interact with cells and ways to use them to stimulate tissues are still active research fronts. This article sets to review the literature on mechanical forces and their role in cutaneous wound healing.