Deferoxamine topical cream superior to patch in rescuing radiation-induced fibrosis of unwounded and wounded skin.

Topical patch delivery of deferoxamine (DFO) has been studied as a treatment for this fibrotic transformation in irradiated tissue. Efficacy of a novel cream formulation of DFO was studied as a RIF therapeutic in unwounded and excisionally wounded irradiated skin. C57BL/6J mice underwent 30 Gy of radiation to the dorsum followed by 4 weeks of recovery. In a first experiment, mice were separated into six conditions: DFO 50 mg cream (D50), DFO 100 mg cream (D100), soluble DFO injections (DI), DFO 1 mg patch (DP), control cream (Vehicle), and irradiated untreated skin (IR). In a second experiment, excisional wounds were created on the irradiated dorsum of mice and then divided into four treatment groups: DFO 100 mg Cream (W-D100), DFO 1 mg patch (W-DP), control cream (W-Vehicle), and irradiated untreated wounds (W-IR). Laser Doppler perfusion scans, biomechanical testing, and histological analysis were performed. In irradiated skin, D100 improved perfusion compared to D50 or DP. Both D100 and DP enhanced dermal characteristics, including thickness, collagen density and 8-isoprostane staining compared to untreated irradiated skin. D100 outperformed DP in CD31 staining, indicating higher vascular density. Extracellular matrix features of D100 and DP resembled normal skin more closely than DI or control. In radiated excisional wounds, D100 facilitated faster wound healing and increased perfusion compared to DP. The 100 mg DFO cream formulation rescued RIF of unwounded irradiated skin and improved excisional wound healing in murine skin relative to patch delivery of DFO.

Successful topical treatment of human biofilms using multiple antibiotic elution from a collagen-rich hydrogel.

Chronic non-healing wounds significantly strain modern healthcare systems, affecting 1-2% of the population in developed countries with costs ranging between $28.1 and $96.8 billion annually. Additionally, it has been established that chronic wounds resulting from comorbidities, such as peripheral vascular disease and diabetes mellitus, tend to be polymicrobial in nature. Treatment of polymicrobial chronic wounds with oral and IV antibiotics can result in antimicrobial resistance, leading to more difficult-to-treat wounds. Ideally, chronic ulcers would be topically treated with antibiotic combinations tailored to the microbiome of a patient's wound. We have previously shown that a topical collagen-rich hydrogel (cHG) can elute single antibiotics to inhibit bacterial growth in a manner that is nontoxic to mammalian cells. Here, we analyzed the microbiology of cultures taken from human patients diagnosed with diabetes mellitus suffering from chronic wounds present for more than 6 weeks. Additionally, we examined the safety of the elution of multiple antibiotics from collagen-rich hydrogel in mammalian cells in vivo. Finally, we aimed to create tailored combinations of antibiotics impregnated into cHG to successfully target and treat infections and eradicate biofilms cultured from human chronic diabetic wound tissue. We found that the majority of human chronic wounds in our study were polymicrobial in nature. The elution of multiple antibiotics from cHG was well-tolerated in mammalian cells, making it a potential topical treatment of the polymicrobial chronic wound. Finally, combinations of antibiotics tailored to each patient's microbiome eluted from a collagen-rich hydrogel successfully treated bacterial cultures isolated from patient samples via an in vitro assay.

Avenanthramide and ß-Glucan Therapeutics Accelerate Wound Healing Via Distinct and Nonoverlapping Mechanisms.

Objective: Given the significant economic, health care, and personal burden of acute and chronic wounds, we investigated the dose dependent wound healing mechanisms of two Avena sativa derived compounds: avenanthramide (AVN) and ß-Glucan. Approach: We utilized a splinted excisional wound model that mimics human-like wound healing and performed subcutaneous AVN and ß-Glucan injections in 15-week-old C57BL/6 mice. Histologic and immunohistochemical analysis was performed on the explanted scar tissue to assess changes in collagen architecture and cellular responses. Results: AVN and ß-Glucan treatment provided therapeutic benefits at a 1% dose by weight in a phosphate-buffered saline vehicle, including accelerated healing time, beneficial cellular recruitment, and improved tissue architecture of healed scars. One percent AVN treatment promoted an extracellular matrix (ECM) architecture similar to unwounded skin, with shorter, more randomly aligned collagen fibers and reduced inflammatory cell presence in the healed tissue. One percent ß-Glucan treatment promoted a tissue architecture characterized by long, thick bundles of collagen with increased blood vessel density. Innovation: AVN and ß-Glucan have previously shown promise in promoting wound healing, although the therapeutic efficacies and mechanisms of these bioactive compounds remain incompletely understood. Furthermore, the healed ECM architecture of these wounds has not been characterized. Conclusions: AVN and ß-Glucan accelerated wound closure compared to controls through distinct mechanisms. AVN-treated scars displayed a more regenerative tissue architecture with reduced inflammatory cell recruitment, while ß-Glucan demonstrated increased angiogenesis with more highly aligned tissue architecture more indicative of fibrosis. A deeper understanding of the mechanisms driving healing in these two naturally derived therapeutics will be important for translation to human use.

Biosensors: An Upcoming Wave of Innovation.

SUMMARY: A biosensor uses a biological molecule to measure a chemical reaction. Wearable biosensors that attach to the body externally, including tooth enamel biosensors, contact lens biosensors, sweat biosensors, and skin tattoo biosensors, are in development. Nanoparticle-based biosensors are being developed to allow for the early detection of cancerous biomarkers. Applications relevant to plastic surgery include the development of biosensors that can detect metastatic breast cancer cells, bioimpedance spectroscopy, and intraoperative point-of-care diagnostics.

Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.

Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing.

Chronic wounds impose a significant healthcare burden to a broad patient population. Cell-based therapies, while having shown benefits for the treatment of chronic wounds, have not yet achieved widespread adoption into clinical practice. We developed a CRISPR/Cas9 approach to precisely edit murine dendritic cells to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing of tolerogenic dendritic cells, we identified N-myc downregulated gene 2 (Ndrg2), which marks a specific population of dendritic cell progenitors, as a promising target for CRISPR knockout. Ndrg2-knockout alters the transcriptomic profile of dendritic cells and preserves an immature cell state with a strong pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a therapeutic hydrogel for in vivo cell delivery and developed an effective translational approach for dendritic cell-based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in dendritic cells for treating various types of chronic wounds.

Robotics in Plastic Surgery: It's Here.

SUMMARY: Although robotic surgery has been routinely established in other surgical disciplines, robotic technologies have been less readily adopted in plastic surgery. Despite a strong demand for innovation and cutting-edge technology in plastic surgery, most reconstructive procedures, including microsurgery, have continued to necessitate an open approach. Recent advances in robotics and artificial intelligence, however, are gaining momentum and have shown significant promise to improve patient care in plastic surgery. These next-generation surgical robots have the potential to enable surgeons to perform complex procedures with greater precision, flexibility, and control than previously possible with conventional techniques. Successful integration of robotic technologies into clinical practice in plastic surgery requires achieving key milestones, including implementing appropriate surgical education and garnering patient trust.

Piezo inhibition prevents and rescues scarring by targeting the adipocyte to fibroblast transition.

While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo -mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to- fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a "mechanically naïve" fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2 -inhibition yields regenerative healing by preventing adipocytes' activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1 -inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo -inhibition in organs where fat contributes to fibrosis.

Chelating the valley of death: Deferoxamine's path from bench to wound clinic.

There is undisputable benefit in translating basic science research concretely into clinical practice, and yet, the vast majority of therapies and treatments fail to achieve approval. The rift between basic research and approved treatment continues to grow, and in cases where a drug is granted approval, the average time from initiation of human trials to regulatory marketing authorization spans almost a decade. Albeit with these hurdles, recent research with deferoxamine (DFO) bodes significant promise as a potential treatment for chronic, radiation-induced soft tissue injury. DFO was originally approved by the Food and Drug Administration (FDA) in 1968 for the treatment of iron overload. However, investigators more recently have posited that its angiogenic and antioxidant properties could be beneficial in treating the hypovascular and reactive-oxygen species-rich tissues seen in chronic wounds and radiation-induced fibrosis (RIF). Small animal experiments of various chronic wound and RIF models confirmed that treatment with DFO improved blood flow and collagen ultrastructure. With a well-established safety profile, and now a strong foundation of basic scientific research that supports its potential use in chronic wounds and RIF, we believe that the next steps required for DFO to achieve FDA marketing approval will include large animal studies and, if those prove successful, human clinical trials. Though these milestones remain, the extensive research thus far leaves hope for DFO to bridge the gap between bench and wound clinic in the near future.

Nitric oxide-releasing gel accelerates healing in a diabetic murine splinted excisional wound model.

Introduction: According to the American Diabetes Association (ADA), 9-12 million patients suffer from chronic ulceration each year, costing the healthcare system over USD $25 billion annually. There is a significant unmet need for new and efficacious therapies to accelerate closure of non-healing wounds. Nitric Oxide (NO) levels typically increase rapidly after skin injury in the inflammatory phase and gradually diminish as wound healing progresses. The effect of increased NO concentration on promoting re-epithelization and wound closure has yet to be described in the context of diabetic wound healing. Methods: In this study, we investigated the effects of local administration of an NO-releasing gel on excisional wound healing in diabetic mice. The excisional wounds of each mouse received either NO-releasing gel or a control phosphate-buffered saline (PBS)-releasing gel treatment twice daily until complete wound closure. Results: Topical administration of NO-gel significantly accelerated the rate of wound healing as compared with PBS-gel-treated mice during the later stages of healing. The treatment also promoted a more regenerative ECM architecture resulting in shorter, less dense, and more randomly aligned collagen fibers within the healed scars, similar to that of unwounded skin. Wound healing promoting factors fibronectin, TGF-ß1, CD31, and VEGF were significantly elevated in NO vs. PBS-gel-treated wounds. Discussion: The results of this work may have important clinical implications for the management of patients with non-healing wounds.

Blockchain, Information Security, Control, and Integrity: Who Is in Charge?

SUMMARY: Blockchain technology has attracted substantial interest in recent years, most notably for its effect on global economics through the advent of cryptocurrency. Within the health care domain, blockchain technology has been actively explored as a tool for improving personal health data management, medical device security, and clinical trial management. Despite a strong demand for innovation and cutting-edge technology in plastic surgery, integration of blockchain technologies within plastic surgery is in its infancy. Recent advances and mainstream adoption of blockchain are gaining momentum and have shown significant promise for improving patient care and information management. In this article, the authors explain what defines a blockchain and discuss its history and potential applications in plastic surgery. Existing evidence suggests that blockchain can enable patient-centered data management, improve privacy, and provide additional safeguards against human error. Integration of blockchain technology into clinical practice requires further research and development to demonstrate its safety and efficacy for patients and providers.

Protocol for the Splinted, Human-like Excisional Wound Model in Mice.

While wound healing in humans occurs primarily through re-epithelization, in rodents it also occurs through contraction of the panniculus carnosus, an underlying muscle layer that humans do not possess. Murine experimental models are by far the most convenient and inexpensive research model to study wound healing, as they offer great variability in genetic alterations and disease models. To overcome the obstacle of contraction biasing wound healing kinetics, our group invented the splinted excisional wound model. While other rodent wound healing models have been used in the past, the splinted excisional wound model has persisted as the most used model in the field of wound healing. Here, we present a detailed protocol of updated and refined techniques necessary to utilize this model, generate results with high validity, and accurately analyze the collected data. This model is simple to conduct and provides an easy, standardizable, and replicable model of human-like wound healing.

Foot Burns and Diabetes: A Systematic Review of Current Clinical Studies and Proposal of a New Treatment Algorithm.

This study aims to systematically identify studies that evaluate lower extremity burn injury in the diabetic population, evaluate their clinical course and patient outcomes, and present a treatment algorithm tailored to diabetic burn patients. Our systematic review of the PubMed and Web of Science databases yielded 429 unique articles. After exclusion and inclusion criteria were applied, 59 articles were selected for evaluation. In diabetic patients, thermal injury was largely a result of decreased awareness and education regarding heat therapies in the context of peripheral neuropathy. All non-case studies found that metrics such as hospital length of stay, ICU admission rates, rates of comorbidity, complication rates, scald injuries, infection rates, and cost of treatment was significantly increased in the diabetic burn population as compared to their nondiabetic counterparts. Where infection was present, microorganisms colonizing diabetic burn wounds were different than those found in the burn wounds of immunocompetent individuals. Operative intervention including split-skin graft, amputation, and debridement were more often utilized in diabetic burn patients. Foot burns in diabetic patients pose unique clinical risks to patients, and as such need to be an alternate treatment protocol to reflect their pathology. Education and training programs are crucial in the prevention of diabetic foot burns to avoid complications, protracted healing, and adverse outcomes. A unique algorithm can guide the unique treatment of this clinical entity.

Denervation during mandibular distraction osteogenesis results in impaired bone formation.

Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn"). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.

Matrix Metalloproteinase-9 as a Potential Biomarker in 631 Human Implant-Induced Fibrotic Capsules: Analysis and Biomarker Study.

BACKGROUND: Capsular fibrosis (CF) often occurs around biomedical devices following implantation causing pain, discomfort, and device failure. Breast implantation remains among the most common medical procedures worldwide. Revealing specific genes that drive fibrotic deposition will help us to garner a better understanding of the pathophysiology of this disease and develop different strategies to combat it. METHODS: The authors collected 631 capsules around breast implants and were able to connect clinical baseline characteristics with histopathologic findings. In addition, the authors were able to conduct the first large systematic analysis to identify differentially expressed genes in fibrotic human tissue samples, comparing the lowest form of fibrosis with the most aggravated one. RESULTS: The authors identified 2559 differentially expressed genes on which they performed a knowledge-based network generation and pathway association study to identify putative novel biomarkers for CF. The authors were able to show changes of cellular influx during progression of CF and distinguish several genes as potential clinical biomarkers and drug targets. Among these, matrix metalloproteinase-9 was one of the most up-regulated ( P = 0.006) and is attractive because of its wide detectability. CONCLUSIONS: Matrix metalloproteinase-9 seems to be a potential biomarker to detect capsular fibrosis. It is a measurable indicator that can easily be detected in blood, sputum, and urine. For the diagnosis of fibrosis, this biomarker might be exceedingly beneficial to developing novel screening methods and prophylaxes. CLINICAL RELEVANCE STATEMENT: Discovering biomarkers at the earliest and mildest stages for the diagnosis of fibrosis is clinically important. These results bring new hope for biomarker-based diagnosis for capsular fibrosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, V.

Multiplexed evaluation of mouse wound tissue using oligonucleotide barcoding with single-cell RNA sequencing.

Despite its rapidly increased availability for the study of complex tissue, single-cell RNA sequencing remains prohibitively expensive for large studies. Here, we present a protocol using oligonucleotide barcoding for the tagging and pooling of multiple samples from healing wounds, which are among the most challenging tissue types for this application. We describe steps to generate skin wounds in mice, followed by tissue harvest and oligonucleotide barcoding. This protocol is also applicable to other species including rats, pigs, and humans. For complete details on the use and execution of this protocol, please refer to Stoeckius et al. (2018),1 Galiano et al. (2004),2 and Mascharak et al. (2022).3.

Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing.

'Smart' bandages based on multimodal wearable devices could enable real-time physiological monitoring and active intervention to promote healing of chronic wounds. However, there has been limited development in incorporation of both sensors and stimulators for the current smart bandage technologies. Additionally, while adhesive electrodes are essential for robust signal transduction, detachment of existing adhesive dressings can lead to secondary damage to delicate wound tissues without switchable adhesion. Here we overcome these issues by developing a flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with skin-interfacing hydrogel electrodes capable of on-demand adhesion and detachment. In mice, we demonstrate that our wound care system can continuously monitor skin impedance and temperature and deliver electrical stimulation in response to the wound environment. Across preclinical wound models, the treatment group healed ~25% more rapidly and with ~50% enhancement in dermal remodeling compared with control. Further, we observed activation of proregenerative genes in monocyte and macrophage cell populations, which may enhance tissue regeneration, neovascularization and dermal recovery.

A bioactive compliant vascular graft modulates macrophage polarization and maintains patency with robust vascular remodeling.

Conventional synthetic vascular grafts are associated with significant failure rates due to their mismatched mechanical properties with the native vessel and poor regenerative potential. Though different tissue engineering approaches have been used to improve the biocompatibility of synthetic vascular grafts, it is still crucial to develop a new generation of synthetic grafts that can match the dynamics of native vessel and direct the host response to achieve robust vascular regeneration. The size of pores within implanted biomaterials has shown significant effects on macrophage polarization, which has been further confirmed as necessary for efficient vascular formation and remodeling. Here, we developed biodegradable, autoclavable synthetic vascular grafts from a new polyurethane elastomer and tailored the grafts' interconnected pore sizes to promote macrophage populations with a pro-regenerative phenotype and improve vascular regeneration and patency rate. The synthetic vascular grafts showed similar mechanical properties to native blood vessels, encouraged macrophage populations with varying M2 to M1 phenotypic expression, and maintained patency and vascular regeneration in a one-month rat carotid interposition model and in a four-month rat aortic interposition model. This innovative bioactive synthetic vascular graft holds promise to treat clinical vascular diseases.

Outcomes of Biosynthetic and Synthetic Mesh in Ventral Hernia Repair.

The introduction of mesh for reinforcement of ventral hernia repair (VHR) led to a significant reduction in hernia recurrence rates. However, it remains controversial whether synthetic or biologic mesh leads to superior outcomes. Recently, hybrid mesh consisting of reinforced biosynthetic ovine rumen (RBOR) has been developed and aims to combine the advantages of biologic and synthetic mesh; however, outcomes after VHR with RBOR have not yet been compared with the standard of care. Methods: We performed a retrospective analysis on 109 patients, who underwent VHR with RBOR (n = 50) or synthetic polypropylene mesh (n = 59). Demographic characteristics, comorbidities, postoperative complications, and recurrence rates were analyzed and compared between the groups. Multivariate logistic regression models were fit to assess associations of mesh type with overall complications and surgical site occurrence (SSO). Results: Patients who underwent VHR with RBOR were older (mean age 63.7 versus 58.8 years, P = 0.02) and had a higher rate of renal disease (28.0 versus 10.2%, P = 0.01) compared with patients with synthetic mesh. Despite an unfavorable risk profile, patients with RBOR had lower rates of SSO (16.0 versus 30.5%, P = 0.12) and similar hernia recurrence rates (4.0 versus 6.78%, P = 0.68) compared with patients with synthetic mesh. The use of synthetic mesh was significantly associated with higher odds for overall complications (3.78, P < 0.05) and SSO (3.87, P < 0.05). Conclusion: Compared with synthetic polypropylene mesh, the use of RBOR for VHR mitigates SSO while maintaining low hernia recurrence rates at 30-month follow-up.