Artificial Intelligence: Singularity Approaches.

SUMMARY: Artificial intelligence (AI) has been a disruptive technology within health care, from the development of simple care algorithms to complex deep-learning models. AI has the potential to reduce the burden of administrative tasks, advance clinical decision-making, and improve patient outcomes. Unlocking the full potential of AI requires the analysis of vast quantities of clinical information. Although AI holds tremendous promise, widespread adoption within plastic surgery remains limited. Understanding the basics is essential for plastic surgeons to evaluate the potential uses of AI. This review provides an introduction of AI, including the history of AI, key concepts, applications of AI in plastic surgery, and future implications.

Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity.

Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.

Vascularized Denervated Muscle Targets for Headache Surgery-Presentation and Surgical Management.

Patients with substantial trauma to their occipital nerves and those with recurrent or persistent chronic headaches after occipital nerve decompression surgery require transection of their greater occipital and/or lesser occipital nerves to control debilitating pain. Current techniques, such as burying the transected nerve stump in nearby muscle, do not prevent neuroma formation, and more advanced techniques, such as targeted muscle reinnervation and regenerative peripheral nerve interface, have demonstrated only short-term anecdotal success in the context of headache surgery. Vascularized denervated muscle targets (VDMTs) are a novel technique to address the proximal nerve stump after nerve transection that has shown promise to improve chronic nerve pain and prevent neuroma formation. However, VDMTs have not been described in the context of headache surgery. Here authors describe the etiology, workup, and surgical management of 2 patients with recurrent occipital neuralgia who developed vexing neuromas after previous surgery and were successfully treated with VDMTs, remaining pain-free at 3-year follow-up.

Treatment of Persistent Post-traumatic Diplopia - An Algorithmic Approach to Patient Stratification and Operative Management.

Study Design: Retrospective chart review of revisional orbital surgery outcomes in patients with diplopia from prior operative treatment of orbital trauma. Objective: Our study seeks to review our experience with management of persistent post-traumatic diplopia in patients with previous orbital reconstruction and present a novel patient stratification algorithm predictive of improved outcomes. Methods: A retrospective chart review was performed on adult patients at Wilmer Eye Institute at Johns Hopkins Hospital and at the University of Maryland Medical Center who underwent revisional orbital surgery for correction of diplopia for the years 2005-2020. Restrictive strabismus was determined by Lancaster red-green testing coupled with computed tomography and/or forced duction. Globe position was assessed by computed tomography. Seventeen patients requiring operative intervention according to study criteria were identified. Results: Globe malposition affected fourteen patients and restrictive strabismus affected eleven patients. In this select group, improvement in diplopia occurred in 85.7% of cases with globe malposition and in 90.1% of cases with restrictive strabismus. One patient underwent additional strabismus surgery subsequent to orbital repair. Conclusions: Post-traumatic diplopia in patients with prior orbital reconstruction can be successfully managed in appropriate patients with a high degree of success. Indications for surgical management include (1) globe malposition and (2) restrictive strabismus. High resolution computer tomography and Lancaster red-green testing discriminate these from other causes that are unlikely to benefit from orbital surgery.

Cybersecurity and Technical Patient Privacy Protection.

Plastic surgery offices are subject to a wide variety of cybersecurity threats, including ransomware attacks that encrypt the plastic surgeon's information and make it unusable, as well as data theft and disclosure attacks that threaten to disclose confidential patient information. Cloud-based office systems increase the attack surface and do not mitigate the effects of breaches that can result in theft of credentials. Although employee education is often recommended to avoid the threats, a single error by a single employee has often led to security breaches, and it is not reasonable to expect that no employee will ever make an error. A recognition of the two most common vectors of these breaches, compromised email attachments and surfing to compromised websites, allows the use of technical networking tools to both prevent email attachments from being received and to prevent employee use of unsanctioned and potentially compromised websites. Further, once compromised code is allowed to run within the office network, that code must necessarily make outbound connections to exploit the breach. Preventing that outbound traffic can mitigate the effects of a breach. However, most small office network consultants design firewalls to only limit incoming network traffic and fail to implement technical measures to stop the unauthorized outbound traffic that is necessary for most network attacks. Detailed techniques are provided which can be used to direct IT consultants to properly limit outbound network traffic as well as incoming email attachments, with more information at https://officenetworksecurity.com.

Colonizing microbiota is associated with clinical outcomes in diabetic wound healing.

With the development of society and the improvement of life quality, more than 500 million people are affected by diabetes. More than 10 % of people with diabetes will suffer from diabetic wounds, and 80 % of diabetic wounds will reoccur, so the development of new diabetic wound treatments is of great importance. The development of skin microbe research technology has gradually drawn people's attention to the complex relationship between microbes and diabetic wounds. Many studies have shown that skin microbes are associated with the outcome of diabetic wounds and can even be used as one of the indicators of wound prognosis. Skin microbes have also been found to have the potential to treat diabetic wounds. The wound colonization of different bacteria can exert opposing therapeutic effects. It is necessary to fully understand the skin microbes in diabetic wounds, which can provide valuable guidance for clinical diabetic wound treatment.

A nanofiber-hydrogel composite improves tissue repair in a rat model of Crohn's disease perianal fistulas.

Perianal fistulas (PAFs) represent a severe complication of Crohn's disease (CD). Despite the advent of biologic and small-molecule therapeutics for luminal disease, PAFs in CD (CD-PAF) are relatively resistant to treatment, with less than 50% responding to any therapy. We report an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of CD-PAF. The ADSC-loaded mfNHC results in a higher degree of healing when compared to surgical treatment of fistulas, which is a standard treatment. The volume of fistulas treated with mfNHC is decreased sixfold compared to the surgical treatment control. Molecular studies reveal that utilization of mfNHC reduced local inflammation and improved tissue regeneration. This study demonstrates that ADSC-loaded mfNHC is a promising therapy for CD-PAF, and warrants further studies to advance mfNHC toward clinical translation.

Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism.

Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called wound-induced hair follicle neogenesis (WIHN), we identified skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multiomic analysis and single-cell RNA sequencing in murine skin, we show that bacterially induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved and coherent physiologic context in which bacterially induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This unexpected proregenerative modulation of metabolism by the skin microbiome in both mice and humans suggests important methods for enhancing regeneration after injury.

A 10-Year Review of Surgical Outcomes at the Johns Hopkins and University of Maryland Resident Aesthetic Clinic.

Background: In 2014, the Plastic Surgery Residency Review Committee of the Accreditation Council for Graduate Medical Education (ACGME) increased minimum aesthetic surgery requirements. Consequently, the resident aesthetic clinic (RAC) has become an ever more important modality for training plastic surgery residents. Objectives: To analyze demographics and long-term surgical outcomes of aesthetic procedures performed at the Johns Hopkins and University of Maryland (JH/UM) RAC. A secondary objective was to evaluate the JH/UM RAC outcomes against those of peer RACs as well as board-certified plastic surgeons. Methods: We performed a retrospective chart review of all patients who underwent aesthetic procedures at the JH/UM RAC between 2011 and 2020. Clinical characteristics, minor complication rates, major complication rates, and revision rates from the JH/UM RAC were compared against 2 peer RACs. We compared the incidence of major complications between the JH/UM RAC and a cohort of patients from the CosmetAssure (Birmingham, AL) database. Pearson's chi-square test was used to compare complication rates between patient populations, with a significance set at 0.05. Results: Four hundred ninety-five procedures were performed on 285 patients. The major complications rate was 1.0% (n = 5). Peer RACs had total major complication rates of 0.2% and 1.7% (P = .07 and P = .47, respectively). CosmetAssure patients matched to JH/UM RAC patients were found to have comparable total major complications rates of 1.8% vs 0.6% (P = .06), respectively. At JH/UM, the minor complication rate was 13.9%, while the revision rate was 5.9%. Conclusions: The JH/UM RAC provides residents the education and training necessary to produce surgical outcomes comparable to peer RACs as well as board-certified plastic surgeons.

Biostimulatory Micro-Fragmented Nanofiber-Hydrogel Composite Improves Mesenchymal Stem Cell Delivery and Soft Tissue Remodeling.

Functional microgels are preferred stem cell carriers due to the ease of delivery through minimally invasive injection and seamless integration with the surrounding host tissue. A biostimulatory nanofiber-hydrogel composite (NHC) has been previously developed through covalently crosslinking a hyaluronic acid hydrogel network with surface-functionalized poly (ε-caprolactone) nanofiber fragments. The NHC mimics the microarchitecture of native soft tissue matrix, showing enhanced cell infiltration, immunomodulation, and proangiogenic properties. Here, injectability of the pre-formed NHC is improved by mechanical fragmentation, making it into micro-fragmented NHC (mfNHC) in a granular gel form as a stem cell carrier to deliver mesenchymal stem cells (MSCs) for soft tissue remodeling. The mfNHC shows a similar storage modulus but a significantly reduced injection force, as compared with the corresponding bulk NHC. When injected subcutaneously in a rat model, mfNHC-MSC constructs initiate an elevated level of host macrophage infiltration, more pro-regenerative polarization, and subsequently, improved angiogenesis and adipogenesis response when compared to mfNHC alone. A similar trend of host cell infiltration and pro-angiogenic response is detected in a swine model with a larger volume injection. These results suggest a strong potential for use of the mfNHC as an injectable carrier for cell delivery and soft tissue remodeling.

Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression.

Lipid nanoparticles hold great potential as an effective non-viral vector for nucleic acid-based gene therapy. Plasmid DNA delivery can result in extended transgene expression compared to mRNA-based technologies, yet there is a lack of systematic investigation into lipid nanoparticle compositions for plasmid DNA delivery. Here, we report a multi-step screening platform to identify optimized plasmid DNA lipid nanoparticles for liver-targeted transgene expression. To achieve this, we analyze the role of different helper lipids and component ratios in plasmid DNA lipid nanoparticle-mediated gene delivery in vitro and in vivo. Compared to mRNA LNPs and in vivo-jetPEI/DNA nanoparticles, the identified plasmid DNA lipid nanoparticles successfully deliver transgenes and mediate prolonged expression in the liver following intravenous administration in mice. By addressing different physiological barriers in a stepwise manner, this screening platform can efficiently down select effective lipid nanoparticle candidates from a lipid nanoparticle library of over 1000 formulations. In addition, we substantially extend the duration of plasmid DNA nanoparticle-mediated transgene expression using a DNA/siRNA co-delivery approach that targets transcription factors regulating inflammatory response pathways. This lipid nanoparticle-based co-delivery strategy further highlights the unique advantages of an extended transgene expression profile using plasmid DNA delivery and offers new opportunities for DNA-based gene medicine applications.

Toward Understanding Wound Immunology for High-Fidelity Skin Regeneration.

Effective tissue repair is vital for the survival of organisms. Yet, how the immune system coordinates with tissue stem cells (SCs) to effect postnatal tissue restoration remains elusive. This review presents current knowledge surrounding wound-induced SC and immune signaling that favors tissue repair, including wound healing and regeneration. We discuss factors that affect regenerative capacities among organisms and the dynamics of local immune cells and SCs during reepithelialization. We also present recent insights into how immune niches communicate with SCs or other body systems to restore the epithelial architecture. Additionally, we summarize our findings on functional wound regeneration, specifically how alarmin (double-stranded RNA [dsRNA])-activated Toll-like receptor signaling and host-microbe interaction-related immune pathways alter the regenerative property of skin SCs. Last, we touch on mechanisms by which known immunologic cellular and molecular signaling might boost the skin's regenerative property. Overall, this review will provide insights into how therapeutically modulating immune signaling could enhance postnatal tissue regeneration.

Mechanical tension mobilizes Lgr6+ epidermal stem cells to drive skin growth.

Uniquely among mammalian organs, skin is capable of marked size change in adults, yet the mechanisms underlying this notable capacity are unclear. Here, we use a system of controlled tissue expansion in mice to uncover cellular and molecular determinants of skin growth. Through machine learning-guided three-dimensional tissue reconstruction, we capture morphometric changes in growing skin. We find that most growth is driven by the proliferation of the epidermis in response to mechanical tension, with more limited changes in dermal and subdermal compartments. Epidermal growth is achieved through preferential activation and differentiation of Lgr6+ stem cells of the epidermis, driven in part by the Hippo pathway. By single-cell RNA sequencing, we uncover further changes in mechanosensitive and metabolic pathways underlying growth control in the skin. These studies point to therapeutic strategies to enhance skin growth and establish a platform for understanding organ size dynamics in adult mammals.

A Markov Analysis of Surgical versus Medical Management of Chronic Migraines.

BACKGROUND: Refractory chronic migraine is a common and debilitating neurologic condition, affecting over 8 million people in the United States. It is associated with billions of dollars in lost productivity annually. Novel medical (anti-calcitonin gene-related peptide antibodies) and surgical treatment modalities have emerged for chronic migraine in recent years. The current study investigated the cost-utility of surgical versus medical management of refractory chronic migraine. METHODS: A Markov cohort analysis using hybrid Monte Carlo patient simulation was performed to compare surgical decompression versus erenumab for the treatment of refractory chronic migraine in adults. Both societal and payer perspectives were considered. Primary model outcomes included incremental cost-effectiveness ratio, or cost per quality-adjusted life-year gained. RESULTS: Over a 5-year period, migraine surgery was associated with an increase of 0.2 quality-adjusted life-year per patient when compared to erenumab. In terms of costs, the results demonstrated a $19,337 decrease in direct medical costs and a $491 decrease in indirect costs (productivity lost) for the surgery cohort compared to erenumab. Because surgery improved quality of life and decreased costs compared to erenumab, even when considering revision surgery needs, surgery was the overall dominant treatment in terms of cost-effectiveness. Sensitivity analyses demonstrated that surgery was cost-effective compared to erenumab when patients required therapy for at least 1 year. CONCLUSIONS: Surgical deactivation of migraine trigger sites may pose a cost-effective approach to treating refractory chronic migraine in adults. This is especially the case when patients are anticipated to require therapy for more than 1 year.

Enrichment of Nanofiber Hydrogel Composite with Fractionated Fat Promotes Regenerative Macrophage Polarization and Vascularization for Soft-Tissue Engineering.

BACKGROUND: Fractionated fat has been shown to promote dermal regeneration; however, the use of fat grafting for reconstruction of soft-tissue defects is limited because of volume loss over time. The authors have developed a novel approach for engineering of vascularized soft tissue using an injectable nanofiber hydrogel composite enriched with fractionated fat. METHODS: Fractionated fat was generated by emulsification of groin fat pads from rats and mixed in a 3:1 ratio with nanofiber hydrogel composite (nanofiber hydrogel composite with fractionated fat). Nanofiber hydrogel composite with fractionated fat or nanofiber hydrogel composite alone was placed into isolation chambers together with arteriovenous loops, which were subcutaneously implanted into the groin of rats (n = 8 per group). After 21 days, animals were euthanized and systemically perfused with ink, and tissue was explanted for histologic analysis. Immunofluorescent staining and confocal laser scanning microscopy were used to quantify CD34+ progenitor cell and macrophage subpopulations. RESULTS: Nanofiber hydrogel composite with fractionated fat tissue maintained its shape without shrinking and showed a significantly stronger functional vascularization compared to composite alone after 21 days of implantation (mean vessel count, 833.5 ± 206.1 versus 296.5 ± 114.1; p = 0.04). Tissue heterogeneity and cell count were greater in composite with fractionated fat (mean cell count, 49,707 ± 18,491 versus 9263 ± 3790; p = 0.005), with a significantly higher number of progenitor cells and regenerative CD163+ macrophages compared to composite alone. CONCLUSIONS: Fractionated fat-enriched nanofiber hydrogel composite transforms into highly vascularized soft tissue over 21 days without signs of shrinking and promotes macrophage polarization toward regenerative phenotypes. Enrichment of injectable nanofiber hydrogel composite with fractionated fat represents a promising approach for durable reconstruction of soft-tissue defects. CLINICAL RELEVANCE STATEMENT: The authors' approach for tissue engineering may ultimately lay the groundwork for clinically relevant applications with the goal of generating large volumes of vascularized soft tissue for defect reconstruction without donor site morbidity.

Size-Controlled and Shelf-Stable DNA Particles for Production of Lentiviral Vectors.

Polyelectrolyte complex particles assembled from plasmid DNA (pDNA) and poly(ethylenimine) (PEI) have been widely used to produce lentiviral vectors (LVVs) for gene therapy. The current batch-mode preparation for pDNA/PEI particles presents limited reproducibility in large-scale LVV manufacturing processes, leading to challenges in tightly controlling particle stability, transfection outcomes, and LVV production yield. Here we identified the size of pDNA/PEI particles as a key determinant for a high transfection efficiency with an optimal size of 400-500 nm, due to a cellular-uptake-related mechanism. We developed a kinetics-based approach to assemble size-controlled and shelf-stable particles using preassembled nanoparticles as building blocks and demonstrated production scalability on a scale of at least 100 mL. The preservation of colloidal stability and transfection efficiency was benchmarked against particles generated using an industry standard protocol. This particle manufacturing method effectively streamlines the viral manufacturing process and improves the production quality and consistency.

Neuroma of The Supraorbital Nerve Following Forehead Flap Reconstruction - Presentation and Surgical Management.

ABSTRACT: Localized pain or headache from neuroma formation is a rare and challenging complication of forehead flap surgery. Here the authors present a patient who developed local pain and dysesthesia following iatrogenic injury to the left supraorbital nerve during forehead flap elevation. Following a diagnostic nerve block in clinic, surgical excision of the neuroma was performed through an upper blepharoplasty approach. The patient had immediate postoperative pain relief and remains pain free at fifteen-month follow-up. The authors describe etiology, workup, and surgical management of sensory nerve injury during forehead flap reconstruction.

Bacteria induce skin regeneration via IL-1ß signaling.

Environmental factors that enhance regeneration are largely unknown. The immune system and microbiome are attributed roles in repairing and regenerating structure but their precise interplay is unclear. Here, we assessed the function of skin bacteria in wound healing and wound-induced hair follicle neogenesis (WIHN), a rare adult organogenesis model. WIHN levels and stem cell markers correlate with bacterial counts, being lowest in germ-free (GF), intermediate in conventional specific pathogen-free (SPF), and highest in wild-type mice, even those infected with pathogenic Staphylococcus aureus. Reducing skin microbiota via cage changes or topical antibiotics decreased WIHN. Inflammatory cytokine IL-1ß and keratinocyte-dependent IL-1R-MyD88 signaling are necessary and sufficient for bacteria to promote regeneration. Finally, in a small trial, a topical broad-spectrum antibiotic also slowed skin wound healing in adult volunteers. These results demonstrate a role for IL-1ß to control morphogenesis and support the need to reconsider routine applications of topical prophylactic antibiotics.

Wound Induced Hair Neogenesis - A Novel Paradigm for Studying Regeneration and Aging.

Hair follicles are the signature dermal appendage of mammals. They can be thought of as mini-organs with defined polarity, distinct constituent cell types, dedicated neurovascular supply, and specific stem cell compartments. Strikingly, some mammals show a capacity for adult hair follicle regeneration in a phenomenon known as wound-induced hair neogenesis (WIHN). In WIHN functional hair follicles reemerge during healing of large cutaneous wounds, and they can be counted to provide an index of regeneration. While age-related decline in hair follicle number and cycling are widely appreciated in normal physiology, it is less clear whether hair follicle regeneration also diminishes with age. WIHN provides an extraordinary quantitative system to address questions of mammalian regeneration and aging. Here we review cellular and molecular underpinnings of WIHN, explore known age-related changes to these elements, and present unanswered questions for future exploration.