Noninvasive treatment of cutaneous neurofibromas (cNFs): Results of a randomized prospective, direct comparison of four methods.

BACKGROUND: People with Neurofibromatosis Type 1 (NF1) suffer disfigurement and pain when hundreds to thousands of cutaneous neurofibromas (cNFs) appear and grow throughout life. Surgical removal of cNFs under anesthesia is the only standard therapy, leaving surgical scars. OBJECTIVE: Effective, minimally-invasive, safe, rapid, tolerable treatment(s) of small cNFs that may prevent tumor progression. METHODS: Safety, tolerability, and efficacy of 4 different treatments were compared in 309, 2-4 mm cNFs across 19 adults with Fitzpatrick skin types (FST) I-IV: radiofrequency (RF) needle coagulation, 755 nm alexandrite laser with suction, 980 nm diode laser, and intratumoral injection of 10 mg/mL deoxycholate. Regional pain, clinical responses, tumor height and volume (by 3D photography) were assessed before, 3 and 6 months post-treatment. Biopsies were obtained electively at 3 months. RESULTS: There was no scarring or adverse events > grade 2. Each modality significantly (P < .05) reduced or cleared cNFs, with large variation between tumors and participants. Alexandrite laser and deoxycholate were fast and least painful; 980 nm laser was most painful. Growth of cNFs was not stimulated by treatment(s) based on height and volume values at 3 and 6 months compared to baseline. LIMITATIONS: Intervention was a single treatment session; dosimetry has not been optimized. CONCLUSIONS: Small cNFs can be rapidly and safely treated without surgery.

Cryolipolysis: The future of cryolipolysis.

BACKGROUND: Cryolipolysis has revolutionized the field of cosmetic dermatology as a nonsurgical procedure, utilizing controlled cooling to selectively destroy fat cells. AIMS AND METHODS: This review article will focus on the future prospects of cryolipolysis, considering advancements in current technology as well as innovations that hold promise for the future. We will explore emerging trends in cryolipolysis, considering novel applicator designs, combination therapies, an innovative injectable treatment approach, and the evolving role of this technology in the field of cosmetic dermatology. CONCLUSION: The future holds promise for advances in cryolipolysis using both the noninvasive topical cooling approach and the novel injectable ice-slurry technology.

Selective reduction of visceral adipose tissue with injectable ice slurry.

Reduction in visceral adipose tissue (VAT) mass reduces body weight and metabolic disease risk in obese patients. However surgical removal of VAT is highly invasive and thus not clinically feasible. We developed an injectable ice slurry for selective reduction of adipose tissue through cryolipolysis. The aim of this study was to investigate safety, feasibility and mechanism of ice slurry-induced cryolipolysis of VAT. Perigonadal VAT in diet-induced obese mice and rats was subjected to slurry or sham treatment. Body weight and blood chemistry were monitored for 56 days post-treatment. Histological analysis and molecular studies were performed to elucidate mechanisms of fat reduction. Treatment of VAT was well tolerated in all animals. Slurry induced adipocyte cell death via selective cryolipolysis; significant weight loss was noted at day 21 post-treatment. RNA sequencing from treated VAT samples showed increased expression of genes involved in inflammation, immune response, collagen biosynthesis and wound healing, and decreased expression of adipokines. This study demonstrates that slurry treatment is safe and effective in inducing cryolipolysis of VAT and subsequent weight loss in mice. Ice slurry is promising as a minimally-invasive treatment to reduce visceral adipose tissue.

Injectable ice slurry for reducing pericardial adipose tissue.

OBJECTIVES: Excess pericardial adipose tissue (PAT) is associated with a higher risk of cardiovascular diseases. Currently, available methods for reducing PAT volume include weight loss through diet and exercise, weight loss with medications, and bariatric surgery. However, these methods are all limited by low patient compliance to maintain the results. We have developed an injectable ice slurry that could selectively target and reduce subcutaneous adipose tissue volume. The aim of this study was to investigate the feasibility and safety of using injectable slurry to selectively reduce PAT volume in a preclinical large animal model. METHODS: PAT in Yucatan swine was injected with slurry or room temperature control solution. All animals were imaged with baseline chest computed tomography (CT) before slurry injection and at 2 months after injection to quantify PAT volume. Specimens from injected and noninjected PAT were harvested for histology. RESULTS: Slurry treatment of PAT was well tolerated in all animals. Slurry-induced selective cryolipolysis in treated PAT. CT imaging showed decrease in PAT volume in treated area at 8 weeks posttreatment compared to baseline, that was significantly different from control solution treated group (median [range]: -29.66 [-35.07 to -27.92]% vs. -1.50 [-11.69 to 8.69]% in control animals respectively, p < 0.05). CONCLUSIONS: This study demonstrated that slurry injection into PAT is feasible in a large animal model. Slurry injection was safe and effective in inducing selective cryolipolysis in PAT and reducing PAT volume. Slurry reduction of PAT could potentially serve as a novel treatment for cardiovascular diseases.

Sunscreens: Misconceptions and Misinformation.

Over the past 70 years, sunscreens have evolved from beach products designed to prevent sunburn to more cosmetically elegant skincare products intended to protect against multiple long-term adverse consequences of characteristically low-intensity daily UV and visible light exposure. Sunscreen testing and labeling intended to quantify such protection are unfortunately often misunderstood by users and have also led to illegal misleading and potentially dangerous industry practices. Changes in regulatory requirements, better policing, and more informative sunscreen labeling would benefit users and their physician advisors.

Total ice content and lipid saturation determine adipose tissue cryolipolysis by injection of ice-slurry.

OBJECTIVES: Cryolipolysis uses tissue cooling to solidify lipids, preferentially damaging lipid-rich cells. Topical cooling is popular for the reduction of local subcutaneous fat. Injection of biocompatible ice-slurry is a recently introduced alternative. We developed and verified a quantitative model that simulates the heat exchange and phase changes involved, offering insights into ice-slurry injection for treating subcutaneous fat. METHODS: Finite element method was used to model the spatial and temporal progression of heat transfer between adipose tissue and injected ice-slurry, estimating dose-response relationships between properties of the slurry and size of tissue affected by cryolipolysis. Phase changes of both slurry and adipose tissue lipids were considered. An in vivo swine model was used to validate the numerical solutions. Oils with different lipid compositions were exposed to ice-slurry in vitro to evaluate the effects of lipid freezing temperature. Microscopy and nuclear magnetic resonance (NMR) were performed to detect lipid phase changes. RESULTS: A ball of granular ice was deposited at the injection site in subcutaneous fat. Total injected ice content determines both the effective cooling region of tissue, and the duration of tissue cooling. Water's high latent heat of fusion enables tissue cooling long after slurry injection. Slurry temperature affects the rate of tissue cooling. In swine, when 30 ml slurry injection at -3.5°C was compared to 15 ml slurry injection at -4.8°C (both with the same total ice content), the latter led to almost twice faster tissue cooling. NMR showed a large decrease in diffusion upon lipid crystallization; saturated lipids with higher freezing temperatures were more susceptible to solidification after ice-slurry injection. CONCLUSIONS: Total injected ice content determines both the volume of tissue treated by cryolipolysis and the cooling duration after slurry injection, while slurry temperature affects the cooling rate. Lipid saturation, which varies with diet and anatomic location, also has an important influence.

Cryoneurolysis with Injectable Ice Slurry Modulates Mechanical Skin Pain.

Cutaneous pain is a common symptom of skin disease, and available therapies are inadequate. We developed a neural selective and injectable method of cryoneurolysis with ice slurry, which leads to a long-lasting decrease in mechanical pain. The aim of this study is to determine whether slurry injection reduces cutaneous pain without inducing the side effects associated with conventional cryoneurolysis. Using the rat sciatic nerve, we examined the effects of slurry on nerve structure and function in comparison with the effects of a Food and Drug Administration‒approved cryoneurolysis device (Iovera). Coherent anti-Stokes Raman scattering microscopy and immunofluorescence staining were used to investigate histological effects on the sciatic nerve and on downstream cutaneous nerve fibers. Complete Freund's Adjuvant model of cutaneous pain was used to study the effect of the slurry on reducing pain. Structural changes in myelin induced by slurry were comparable with those induced by Iovera, which uses much colder temperatures. Compared with that of Iovera, the decrease in mechanical pain due to slurry was less profound but lasted longer without signs of dysesthesia. Slurry did not cause a reduction of epidermal nerve fibers or a change in thermal pain sensitivity. Slurry-treated rats showed reduced cutaneous mechanical pain in response to Complete Freund's Adjuvant. Slurry injection can be used to successfully reduce cutaneous pain without causing dysesthesia.

Innovating on innovation training with the Virtual Magic Wand (VMW) program: a qualitative study.

To identify and solve unmet needs and bring new therapies to patients, clinicians at all levels must engage in innovation. The Magic Wand Initiative, a program based at Massachusetts General Hospital-Wellman Center for Photomedicine, created a 10-months course called the Virtual Magic Wand (VMW) program that is a curriculum that teaches the biomedical innovation pathway to dermatologists and engages them in this creative process. This study aims to identify the impact of the VMW program on participants and consider the potential benefits of an innovation curriculum. The authors conducted semi-structured interviews in which alumni of the VMW program were asked about their experiences with innovation before, during, and after the program. Using grounded theory methodology, data were analyzed using deductive coding methods. The most cited benefit of the program was the opportunity to network (n = 12, 100%)-specifically, the mentorship opportunities (n = 10, 83%) and specialty-specific peer groups (n = 9, 75%). Other benefits included a change in mindset regarding their clinical work (n = 11, 92%) and learning the process of innovation (83%). Among barriers, lack of time (n = 7, 58%), knowledge (n = 6, 50%), and resources (n = 5, 42%), were the most mentioned. All alumni interviewed have stayed engaged in the field of biomedical innovation after their completion of the VMW program. These findings show that the VMW program positively impacted the lives and careers of participants. This study identified some of the systemic reasons that deter physicians from regularly engaging in innovation and provides guidance for how to design other innovation programs and further support the advancement of medicine.

Fast-acting and injectable cryoneurolysis device.

Cryoneurolysis is an opioid-sparing therapy for long-lasting and reversible reduction of pain. We developed a nerve-selective method for cryoneurolysis by local injection of ice-slurry (- 5 to - 6 °C) that induced decrease in nocifensive response starting from about a week after treatment and lasting up to 8 weeks. In this study, we test the hypothesis that injection of colder slurry leads to faster onset of analgesia. Colder slurry (- 9ºC) was injected around the rat sciatic nerve to induce cryoneurolysis. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on surrounding tissues. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths. Functional tests were used to assess changes in sensory and motor function in the treated hind paw. No inflammation or scarring was detected in surrounding skin and muscle tissues at day 7 post slurry injection. Functional tests showed rapid onset reduction in mechanical pain sensitivity starting from day 1 and lasting up to day 98. CARS imaging demonstrated disintegration of myelin sheaths post treatment followed by complete recovery of nerve structure by day 140. In this study we showed that colder slurry (- 9 °C) produces more rapid onset and longer duration of analgesia, while remaining nerve-selective.

Safety and feasibility of selective tongue fat reduction with injected ice-slurry.

Objectives: There is growing evidence that excess adipose tissue within the head and neck contributes to obstructive sleep apnea (OSA), particularly in obese patients. This subset of the population is often difficult to treat with surgical therapies. We theorized that a novel, transcervical method of injectable cryoablation using ice-slurry can achieve low temperatures without causing neurovascular damage or airway distress in a swine model. Methods: Four Yorkshire pigs were injected with ice-slurry comprised of normal saline and 10% glycerol cooled to -6°C via a transcervical, ultrasound guided approach. Direct laryngoscopy was used to confirm accurate placement of the slurry. Thermocouple placement at the needle-tip was used to measure temperatures at injection site. Swine were monitored for clinical signs of tongue necrosis and airway edema for 2 months, and then euthanized. Twelve biopsy samples from the base of the tongue were collected for histology. These were assessed for presence of tissue damage, inflammation and collagen formation by a blinded board-certified pathologist. Results: Tongue tissue temperature below 10°C was achieved for 13.5 ± 1.1 min. Minimum tissue temperature was -4 ± 0.6°C. There was no clinical or pathological evidence of tongue damage to include damage to the lingual nerve or artery. There was some histologic evidence of new collagen formation in areas of the tongue. Conclusions: Transcervical ultrasound-guided ice-slurry injection is feasible, well-tolerated at temperatures previously shown to be capable of selectively targeting adipose tissue in the base of the tongue in a preclinical swine model, without causing neurovascular damage or airway distress when properly injected.

Full Recovery after Multiple Treatments with Injectable Ice Slurry.

Background: Cryoneurolysis uses tissue cooling as an opioid-sparing, long-lasting treatment for peripheral nerve pain. A nerve-selective method for cryoneurolysis by local injection of ice-slurry was developed to allow cryoneurolysis to be performed with a standard needle and syringe, similar to peripheral nerve blocks. Since the treatment of patients with chronic pain may require repeated injections, we investigated the safety and tolerance of repeated treatments in a rat model. Methods: Three repeated ice-slurry treatments, given 6 weeks apart were performed around the rat sciatic nerve. Nerve and surrounding tissues were collected up to 4 months after the third treatment for analysis. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths and axon structure. Immunofluorescence (IF) staining was used to study effects on axon density. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on sciatic nerve and surrounding tissue. Results: Histologic and CARS image analysis of nerve tissue collected months after three injections demonstrated recovery of nerve structure, myelin organization and axon density to baseline levels, without any residual inflammation, scarring or neuroma formation. No inflammation or scarring was detected in surrounding skin and muscle tissues. Conclusion: Repeated ice-slurry injections cause temporary, nerve-selective and reversible changes in the peripheral nerve. There was no histologic damage to surrounding skin and muscle tissues. Repeated treatments with injectable ice-slurry for cryoneurolysis appear to be safe and well tolerated. Clinical studies for patients with chronic pain are warranted.

Skin of color representation in cosmetic clinical trials: A literature review.

Despite cosmetic procedures being on the rise in the US in all demographics, cosmetic procedures remain heavily skewed towards non-skin of color patients. Cosmetic clinical trials in the United States must be representative of the ever-increasing diversity of the US population. We sought to analyze published cosmetic randomized controlled trials, both industry-sponsored and investigator-initiated, to characterize and assess representation of skin of color participants over the past three decades. Our study shows that industry sponsorship correlates with poor study participant ethnic/racial diversity in aesthetic randomized controlled trials, and should serve as a call to action for industries to increase the inclusion of skin of color participants in their studies.

The Potential of CRISPR-Guided Therapies in the Dermatology Clinic.

Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist.

A call to action: why medical education curriculum needs to encourage young physicians to innovate.

Patient-centered and physician-led innovations are key to promoting physicians as visionary leaders in the healthcare system especially during times of crises. COVID-19 has inspired some promising recent advancements within medicine worth noting, including improvements in telemedicine, 3-D printed personal protective equipment (PPE) and ventilators, drug and vaccine development, sterilization of PPE allowing for reuse, and point of care testing; they highlight a broader lesson for how we might innovate better within medicine, even after the crisis has passed. As such, with the complexities of modern-day medicine, to continue to foster this culture of innovation, it is paramount that going forward, medical education adapt and embrace an innovation curriculum that prepares physicians and healthcare workers to work with their communities and researchers to confidently tackle any challenges that may present. Integrating innovation into our careers and medical training is important for advancement of the field and to be able to handle challenges that may present to the healthcare system.