The Mechanism of Cannabichromene and Cannabidiol Alone Versus in Combination in the Alleviation of Arthritis-Related Inflammation.

BACKGROUND: Patients suffering from arthritis have limited treatment options for nonoperative management. In search of pain relief, patients have been taking over-the-counter cannabinoids. Cannabidiol (CBD) and cannabichromene (CBC) are minor cannabinoids with reported analgesic and anti-inflammatory properties and have been implicated as potential therapeutics for arthritis-related pain. To this end, we utilized a murine model to investigate the effectiveness of and mechanism by which CBC alone, CBD alone, or CBD and CBC in combination may provide a reduction in arthritis-associated inflammation. METHODS: Forty-eight mice were included in the study, which were separated into 4 groups: control group (n = 12), treatment with CBD alone (n = 12), treatment with CBC alone (n = 12), and treatment with CBD + CBC (n = 12). We induced inflammation in each mouse utilizing the collagen-induced arthritis model. At scheduled timepoints, mice were clinically assessed for weight gain, swelling, and arthritis severity. In addition, inflammation-associated serum cytokine levels were analyzed for each animal. RESULTS: Thirty-five of 48 mice survived the duration of the study resulting in the following group numbers: control group (n = 8), treatment with CBD alone (n = 9), treatment with CBC alone (n = 9), and treatment with CBD + CBC (n = 9). Animals treated with CBC and CBD + CBC showed significant weight gain between 3 and 5 weeks. Irrespective of treatment, regression analysis comparing all cytokine measurement and physical outcomes found a significant positive correlation between levels of 5 individual cytokines and both arthritis scores and swelling. Animals treated with CBD + CBC showed a significant decrease in swelling between 3 and 5 weeks compared with the control group. Cannabinoid treatment selectively affected the gene expression of eotaxin and lipopolysaccharide-induced CXC chemokine with combined treatment of CBC + CBD. CONCLUSION: Treatment with cannabinoids resulted in decreased clinical markers of inflammation. Further, the anti-inflammatory effect of CBC and CBD in conjunction was associated with a greater anti-inflammatory effect than either minor cannabinoid alone. Future work will elucidate the possibility of synergistic or entourage effects of minor cannabinoids used in combination for the treatment of arthritis-related pain and inflammation.

De novo tissue formation using custom microporous annealed particle hydrogel provides long-term vocal fold augmentation.

Biomaterial-enabled de novo formation of non-fibrotic tissue in situ would provide an important tool to physicians. One example application, glottic insufficiency, is a debilitating laryngeal disorder wherein vocal folds do not fully close, resulting in difficulty speaking and swallowing. Preferred management of glottic insufficiency includes bulking of vocal folds via injectable fillers, however, the current options have associated drawbacks including inflammation, accelerated resorption, and foreign body response. We developed a novel iteration of microporous annealed particle (MAP) scaffold designed to provide persistent augmentation. Following a 14-month study of vocal fold augmentation using a rabbit vocal paralysis model, most MAP scaffolds were replaced with tissue de novo that matched the mixture of fibrotic and non-fibrotic collagens of the contralateral vocal tissue. Further, persistent tissue augmentation in MAP-treated rabbits was observed via MRI and via superior vocal function at 14 months relative to the clinical standard.

A Simple and Reproducible In Vivo Rabbit Phonation Model for Glottic Insufficiency.

OBJECTIVE: The objective of this study is to describe an in vivo rabbit phonation model for glottic insufficiency that is simple and reproducible by means of unilateral transcricothyroid laryngeal muscle stimulation and high-speed video recordings of evoked phonation. STUDY DESIGN: Nonrandomized controlled animal trial. SETTING: Academic medical center. METHODS: A single operation including evoked phonation with bilateral and unilateral transcricothyroid laryngeal muscle stimulation conditions was modeled using 6 New Zealand white rabbits. The effect of stimulation method on glottic cycle, pitch, and loudness was compared. Endoscopic recordings using 5000 frames-per-second image capture technology and audiologic recordings were obtained for all phonation conditions. Primary outcome measures included means of maximum glottal area (MGA)/length pixel ratio, right and left amplitude/length pixel ratios, calculated cycle frequency, auditory recorded frequency, and maximum auditory intensity. Measurements were obtained via pixel counts using ImageJ. RESULTS: Mean MGA/length was significantly greater with unilateral, 20.30, vs bilateral, 9.62, stimulation (P = .043). Mean frequency of 479.92 Hz vs 683.46 Hz (P = .027) and mean maximum intensity of 76.3 dB vs 83.5 dB (P = .013) were significantly increased from unilateral to bilateral stimulation. There was no significant difference in mean right amplitude/length between unilateral and bilateral. CONCLUSION: The described model demonstrates a simple and reproducible means of producing glottic insufficiency due to unilateral vocal fold bowing and represents a pathway for better understanding the biomechanics and pathophysiology of glottic insufficiency due to superior laryngeal nerve injury and vocal fold immobility and offers the potential to compare treatment modalities through in vivo study.

Acellular Dermal Matrix Favorably Modulates the Healing Response after Surgery.

SUMMARY: When first described for breast reconstruction, the presence of acellular dermal matrices was associated with increased seroma formation and infection. However, clinical safety data have gradually improved with surgeon experience to an acceptable outcomes profile of acellular dermal matrix-assisted reconstruction when compared to submuscular implant coverage. In fact, acellular dermal matrix use potentially decreases capsular contracture rates and facilitates expansion for staged prepectoral breast reconstruction. Because of new regulatory requirements, the collection of unbiased, well-powered premarket approval data summarizing long-term clinical outcomes will be essential over the coming years to understand the clinical performance of acellular dermal matrix use in breast reconstruction. Currently, the authors can highlight the physiologic benefits of acellular dermal matrix use in breast reconstruction by evaluating the components of surgical wound healing that are favorably augmented by the implanted collagen substrate. Acellular dermal matrix takes advantage of the wound healing cascade to incorporate into the patient's tissues-a process that requires a coordinated inflammatory infiltrate and angiogenesis. The presence of acellular dermal matrix augments and modulates the wound healing process to its advantage by simultaneously increasing the invasion of appropriate cellular constituents to facilitate expeditious healing and accelerate angiogenesis. In this article, the authors summarize the wound healing literature to demonstrate the mechanisms acellular dermal matrices use to biointegrate and the literature in which cellular constituents and soluble growth factors are up-regulated in the presence of acellular dermal matrix. Lastly, the authors use their experimental observations of acellular dermal matrix incorporation to corroborate the literature.

A Randomized Controlled Trial of Topical Cannabidiol for the Treatment of Thumb Basal Joint Arthritis.

PURPOSE: Since the passage of the Agricultural Improvement Act of 2018, hand surgeons have increasingly encountered patients seeking counseling on over-the-counter, topical cannabidiol (CBD) for the treatment of pain. To this end, we designed a human clinical trial to investigate the therapeutic potential of CBD for the treatment of pain associated with thumb basal joint arthritis. METHODS: Following Food and Drug Administration and institutional approval, a phase 1 skin test was completed with 10 healthy participants monitored for 1 week after twice-daily application of 1 mL of topical CBD (6.2 mg/mL) with shea butter. After no adverse events were identified, we proceeded with a phase 2, double-blinded, randomized controlled trial. Eighteen participants with symptomatic thumb basal joint arthritis were randomized to 2 weeks of twice-daily treatment with CBD (6.2 mg/mL CBD with shea butter) or shea butter alone, followed by a 1-week washout period and then crossover for 2 weeks with the other treatment. Safety data and physical examination measurements were obtained at baseline and after completion of each treatment arm. RESULTS: Cannabidiol treatment resulted in improvements from baseline among patient-reported outcome measures, including Visual Analog Scale pain; Disabilities of the Arm, Shoulder, and Hand; and Single Assessment Numeric Evaluation scores, compared to the control arm during the study period. There were similar physical parameters identified with range of motion, grip, and pinch strength. CONCLUSIONS: In this single-center, randomized controlled trial, topical CBD treatment demonstrated significant improvements in thumb basal joint arthritis-related pain and disability without adverse events. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Immunomodulation of Acellular Dermal Matrix Through Interleukin 4 Enhances Vascular Infiltration.

BACKGROUND: Acellular dermal matrix (ADM) supported implant-based reconstruction remains the most commonly performed mode of reconstruction after breast cancer. Acellular dermal matrix clinical usage has reported benefits but requires rapid and efficient vascular and cellular incorporation into the recipient to have the best outcomes. Orderly transition from M1 to M2 macrophage phenotypic profile, coordinated in part by interleukin 4 (IL-4), is an important component of vascular stabilization and remodeling. Using the ADM substrate as a delivery device for immunomodulation of macrophage phenotype holds the potential to improve integration. METHODS: Interleukin 4 was adsorbed onto ADM samples and drug elution curves were measured. Next, experimental groups of 8 C57BL/6 mice had 5-mm ADM discs surgically placed in a dorsal window chamber with a vascularized skin flap on one side and a plastic cover slip on the other in a model of implant-based breast reconstruction. Group 1 consisted of IL-4 (5 µg) adsorbed into the ADM preoperatively and group 2 consisted of an untreated ADM control. Serial gross examinations were performed with histology at day 21 for markers of vascularization, mesenchymal cell infiltration, and macrophage lineage. RESULTS: Drug elution curves showed sustained IL-4 release for 10 days after adsorption. Serial gross examination showed similar rates of superficial vascular investment of the ADM beginning at the periphery by day 14 and increasing through day 21. Interleukin-4 treatment led to significantly increased CD31 staining of vascular endothelial cells within the ADM over the control group (P < 0.05) at 21 days. Although vimentin staining did not indicate a significant increase in fibroblasts overall, IL-4 did result in a significant increase in expression of α-smooth muscle actin. The expression of macrophage phenotype markers Arginase1 and iNOS present within the ADM were not significantly affected by IL-4 treatment at the day 21 time point. CONCLUSIONS: Acellular dermal matrix has the potential to be used for immunomodulatory cytokine delivery during the timeframe of healing. Using implanted ADM as a delivery vehicle to drive IL-4 mediated angiogenesis and vascular remodeling significantly enhanced vascularity within the ADM substrate.

Local estrogen for nonsurgical recontouring of auricular cartilage.

INTRODUCTION: 5% of children are born with auricular deformities. Permanent recontouring can be achieved through splinting during early infancy. Beyond this time, splinting is ineffective, and patients require surgical correction. Neonatal cartilage malleability is hypothesized to be secondary to retained maternal estrogens, increasing hyaluronic acid concentration. In this article, we evaluate the efficacy of local estrogen treatments for the nonsurgical recontouring of mature auricular cartilage. METHODS: Ears of New Zealand rabbits were folded and splinted and then were randomly assigned to an experimental group, n = 10 (injected estrogen, topical estrogen, saline, or untreated). Treatment ears received injected estrogen or saline twice weekly or topical estrogen daily for 4 weeks. Two weeks post-treatment, splints were removed, and ear angles were measured. Biopsies were taken for histologic and mechanical analysis, and systemic estrogen levels were assayed. RESULTS: Ear angles stabilized by 9 days post-splinting. Topical estrogen led to a significantly smaller resting angle (121.6° ± 13.5°) compared with saline and control (135.9° ± 11.2° and 145.3° ± 13.0°, respectively). Injected estrogen led to the most pronounced angle decrease (64.5° ± 35.3°). Ears injected with estrogen also showed a significant increase in cartilage thickness. Hyaluronic acid concentration was increased in both estrogen treatment groups compared with saline. At 3 weeks post-treatment, there was no significant differences in the elastic modulus of the cartilage or serum estrogen levels among the groups. CONCLUSION: Results show the potential result of local estrogen treatment to achieve a stable nonsurgical remodeling of mature auricular cartilage. Further study is needed to evaluate the molecular mechanism and improve the transdermal estrogen delivery to optimize treatment regimen.

Effect of Temperature and Freezing on Human Adipose Tissue Material Properties Characterized by High-Rate Indentation: Puncture Testing.

The characterization of human subcutaneous adipose tissue (SAT) under high-rate loading is valuable for development of biofidelic finite element human body models (FE-HBMs) to predict seat belt-pelvis interaction and injury risk in vehicle crash simulations. While material characterization of SAT has been performed at 25 °C or 37 °C, the effect of temperature on mechanical properties of SAT under high-rate and large-deformation loading has not been investigated. Similarly, while freezing is the most common preservation technique for cadaveric specimens, the effect of freeze-thaw on the mechanical properties of SAT is also absent from the literature. Therefore, the aim of this study was to determine the effect of freezing and temperature on mechanical properties of human SAT. Fresh and previously frozen human SAT specimens were obtained and tested at 25 °C and 37 °C. High-rate indentation and puncture tests were performed, and indentation-puncture force-depth responses were obtained. While the chance of material failure was found to be different between temperatures and between fresh and previously frozen tissue, statistical analyses revealed that temperature and freezing did not change the shear modulus and failure characteristics of SAT. Therefore, the results of the current study indicated that SAT material properties characterized from either fresh or frozen tissue at either 25 °C or 37 °C could be used for enhancing the biofidelity of FE-HBMs.

Multidirectional mechanical properties and constitutive modeling of human adipose tissue under dynamic loading.

The mechanical behavior of subcutaneous adipose tissue (SAT) affects the interaction between vehicle occupants and restraint systems in motor vehicle crashes (MVCs). To enhance future restraints, injury countermeasures, and other vehicle safety systems, computational simulations are often used to augment experiments because of their relative efficiency for parametric analysis. How well finite element human body models (FE-HBMs), which are often used in such simulations, predict human response has been limited by the absence of material models for human SAT that are applicable to the MVC environment. In this study, for the first time, dynamic multidirectional unconfined compression and simple shear loading tests were performed on human abdominal SAT specimens under conditions similar to MVCs. We also performed multiple ramp-hold tests to evaluate the quasilinear viscoelasticity (QLV) assumption and capture the stress relaxation behavior under both compression and shear. Our mechanical characterization was supplemented with scanning electron microscopy (SEM) performed in different orientations to investigate whether the macrostructural response can be related to the underlying microstructure. While the overall structure was shown to be visually different in different anatomical planes, a preferred orientation of any fibrous structures could not be identified. We showed that the nonlinear, viscoelastic, and direction-dependent responses under compression and shear tests could be captured by incorporating QLV in an Ogden-type hyperelastic model. Our comprehensive approach will lead to more accurate computational simulations and support the collective effort on the research of future occupant protection systems. STATEMENT OF SIGNIFICANCE: There is an urgent need to characterize the mechanical behavior of human adipose tissue under multiple dynamic loading conditions, and to identify constitutive models that are able to capture the tissue response under these conditions. We performed the first series of experiments on human adipose tissue specimens to characterize the multi-directional compression and shear behavior at impact loading rates and obtained scanning electron microscope images to investigate whether the macrostructural response can be related to the underlying microstructure. The results showed that human adipose tissue is nonlinear, viscoelastic and direction dependent, and its mechanical response under compression and shear tests at different loading rates can be captured by incorporating quasi-linear viscoelasticity in an Ogden-type hyperelastic model.

The mechanical and microstructural properties of the pediatric skull.

The pediatric skull differs drastically from the adult skull in terms of composition, rigidity, and structure. However, there is limited data which quantifies the mechanical properties of the pediatric skull. The lack of mechanical data may inhibit desired pediatric craniofacial surgical outcomes as current methodologies and materials employed for the pediatric population are adapted from those used for adults. In this study, normally discarded parietal bone tissue from eight pediatric craniosynostosis surgery patients (aged 4 to 10 months) was collected during reconstructive surgery and prepared for microstructural analysis and mechanical testing. Up to 12 individual coupon samples of fresh, never frozen tissue were harvested from each specimen and prepared for four-point bending testing to failure. The microstructure of each sample was analyzed using micro-computed tomography before and after each mechanical test. From this analysis, effective geometric and mechanical properties were determined for each sample (n = 68). Test results demonstrated that the pediatric parietal skull was 2.0 mm (±0.4) thick, with a porosity of 36% (±14). The effective modulus of the tissue samples, determined from the initial slope of the sample stress-strain response using Euler beam theory and a nonlinear Ramberg-Osgood stress-strain relationship, was 4.2 GPa (±2.1), which was approximately three times less stiff than adult skull tissue reported in the literature. Furthermore, the pediatric skull was able to bend up to flexural failure strains of 6.7% (±2.0), which was approximately five times larger than failure strains measured in adult skull. The disparity between the measured mechanical properties of pediatric skull tissue and adult skull tissue points towards the need to reevaluate current surgical technologies, such as pediatric cranial surgical hardware, so that they are more compatible with pediatric tissue.

In Vitro Mechanical Characterization and Modeling of Subcutaneous Adipose Tissue: A Comprehensive Review.

Mechanical models of adipose tissue are important for various medical applications including cosmetics, injuries, implantable drug delivery systems, plastic surgeries, biomechanical applications such as computational human body models for surgery simulation, and blunt impact trauma prediction. This article presents a comprehensive review of in vivo experimental approaches that aimed to characterize the mechanical properties of adipose tissue, and the resulting constitutive models and model parameters identified. In particular, this study examines the material behavior of adipose tissue, including its nonlinear stress-strain relationship, viscoelasticity, strain hardening and softening, rate-sensitivity, anisotropy, preconditioning, failure behavior, and temperature dependency.

Oxygen-Sensing Biomaterial Construct for Clinical Monitoring of Wound Healing.

OBJECTIVE: Oxygen is essential to wound healing; therefore, accurate monitoring can guide clinical decisions. Clinical wound assessment is often subjective, and tools to monitor wound oxygen are typically expensive, indirect, and highly variable. This study demonstrates the utility of a novel, low-cost oxygen-sensing thin film for serial assessment of wound oxygenation. DESIGN: Dual-layer films were fabricated with boron oxygen-sensing nanoparticles (BNPs) impregnated into a chitosan-polycaprolactone layer for direct wound bed contact with a relatively oxygen impermeable calcium alginate surface layer. The BNPs are a dual-emissive difluoroboron ß-diketonate dye incorporated into poly(lactic acid) nanoparticles. Under UV excitation, the BNPs emit fluorescence based on concentration and oxygen-sensitive phosphorescence. The fluorescence/phosphorescence ratio is directly proportional to oxygen concentration. METHODS: A series of in vitro oxygen challenges and in vivo murine and porcine wound healing models were used to validate the utility of the film in sensing wound oxygenation. MAIN RESULTS: In vitro testing demonstrated the oxygen-sensing capability of the BNP film and its ability to shield ambient oxygen to isolate wound oxygen. In vivo testing demonstrated the ability of the film to accurately monitor relative oxygen changes in a murine wound over time, measuring a 22% fluorescence/phosphorescence increase during acute healing. CONCLUSIONS: This study presents a low-cost, noninvasive, direct, and serial oxygen mapping technology to detect spatial differences in wound oxygenation. Clinical use of the films has the potential to monitor wound healing trajectories and guide wound care decisions.

The Biointegration of a Porcine Acellular Dermal Matrix in a Novel Radiated Breast Reconstruction Model.

BACKGROUND: Ideal acellular dermal matrices (ADM) for breast reconstruction exhibit native extracellular matrix (ECM) structure to allow rapid biointegration and appropriate mechanical properties for desired clinical outcomes. In a novel in vivo model of irradiated breast reconstruction, we describe the cellular and vascular ingrowth of Artia, a porcine product chemically prepared to mimic the biomechanics of human ADM, with retained natural ECM structure to encourage cellular ingrowth. METHODS: Utilizing the murine dorsal skinfold model, Artia was implanted into 16 C57bl/6 mice. Eight of the mice received a single dose 35 Gy radiation to the skin, followed by 12 weeks to produce radiation fibrosis and 8 mice served as nonradiated controls. Real-time photoacoustic microscopy of vascular integration and oxygen saturation within the ADM were made over 14 days. At 21 days, vascular ingrowth (CD31), fibroblast scar tissue formation (alpha smooth-muscle actin α-SMA, vimentin), and macrophage function (M2/M1 ratio) were evaluated. Scanning electron microscopy images of Artia were produced to help interpret the potential orientation of cellular and vascular ingrowth. RESULTS: Repeated photoacoustic microscopy imaging demonstrated vascular ingrowth increasing over 14 days, with a commensurate increase in oxygen saturation within both radiated and nonradiated ADM-albeit at an insignificantly lower rate in the radiated group. By day 21, robust CD31 staining was seen that was insignificantly greater in the nonradiated group. Of the fibroblast markers, vimentin expression was significantly greater in the radiated group (P < 0.05). Macrophage lineage phenotype was consistent with remodeling physiology in both radiated and nonradiated groups. Scanning electron microscopy demonstrated transversely organized collagen fibrils with natural porous ECM structure to allow cellular ingrowth. CONCLUSIONS: Artia demonstrates appropriate biointegration, with increased oxygen saturation by 14 days, consistent with the performance of other collagen substrates in this model. Radiation fibrosis resulted in higher vimentin expression yet did not impact macrophage phenotype while only modestly decreasing Artia biointegration suggesting that ADM may have a role in reconstructive efforts in a radiated setting. Taken together with its enhanced biomechanics, this porcine ADM product is well poised to be clinically applicable to breast reconstruction.

Injectable Microannealed Porous Scaffold for Articular Cartilage Regeneration.

BACKGROUND: The purpose of this study is to assess the feasibility of a novel microporous annealed particle (MAP) scaffolding hydrogel to enable both articular cartilage and subchondral bone biointegration and chondrocyte regeneration in a rat knee osteochondral defect model. METHODS: An injectable, microporous scaffold was engineered and modified to match the mechanical properties of articular cartilage. Two experimental groups were utilized-negative saline control and MAP gel treatment group. Saline and MAP gel were injected into osteochondral defects created in the knees of Sprague-Dawley rats. Photo-annealing of the MAP gel was performed. Qualitative histologic and immunohistochemical analysis was performed of the treated defects at 2, 4, and 8 weeks postsurgery. RESULTS: The injectable MAP gel successfully annealed and was sustained within the osteochondral defect at each timepoint. Treatment with MAP gel resulted in maintained size of the osteochondral defect with evidence of tissue ingrowth and increased glycosaminoglycan production, whereas the control defects presented with evidence of disorganized scar tissue. Additionally, there was no significant inflammatory response to the MAP gel noted on histology. CONCLUSIONS: We have demonstrated the successful delivery of an injectable, flowable MAP gel scaffold into a rat knee osteochondral defect with subsequent annealing and stable integration into the healing wound. The flowable nature of this scaffold allows for minimally invasive application, for example, via an arthroscopic approach for management of wrist arthritis. The MAP gel was noted to fill the osteochondral defect and maintain the defect dimensions and provide a continuous and smooth surface for cartilage regeneration, suggesting its ability to provide a stable scaffold for tissue ingrowth. Future chemical, mechanical, and biological gel modifications may improve objective evidence of cartilage regeneration.

Development of a microporous annealed particle hydrogel for long-term vocal fold augmentation.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to develop and provide evidence of a novel permanent injectable biomaterial for vocal fold augmentation with the potential to treat glottic incompetence by evaluating its performance in two animal models. STUDY DESIGN: Animal model. METHODS: Microporous annealed particle (MAP) hydrogel was fabricated using a water-in-oil emulsion method and synthetically tuned to match the stiffness modulus of native vocalis muscle. Thirty-two New Zealand White rabbits were administered unilateral injections of MAP (n = 16), saline (n = 8), and the clinical standard hyaluronic acid (Restylane-L) (n = 8), and evaluated at day 0, and 6-week, 4-month, and 6-month endpoints. Induced vocal fold vibration was recorded with a high-speed camera prior to euthanization, with glottic closure and mucosal wave characteristics assessed both quantitatively and qualitatively by an experienced voice clinician. Histologic analysis was performed to assess scaffold permanence, immunogenicity, and vascularization within the scaffold. RESULTS: Histologic analysis confirmed the MAP gel treatment group maintained its volume without migration for 6 months postimplantation. Immune staining showed minimal to nonexistent immunogenicity over the course of the implant lifetime. Extensive tissue integration and vascularization was observed histologically within the MAP gel group by immunofluorescence staining. Mucosal wave was not impaired by any of the injected materials, including the MAP gel augmentation. CONCLUSIONS: MAP gel is a nonresorbable biostimulatory injectable implant that provides superior tissue integration, stiffness matching, and permanence compared to current injectable implants, with retained biomechanical function, suggesting its potential as a new therapeutic for glottic incompetence. LEVEL OF EVIDENCE: NA Laryngoscope, 130:2432-2441, 2020.

The Use of Patient-Specific Three-Dimensional Printed Surgical Models Enhances Plastic Surgery Resident Education in Craniofacial Surgery.

PURPOSE: A significant challenge in surgical education is to provide a meaningful hands-on experience with the pathology the trainee will see in independent practice. Craniofacial anatomy is challenging and unfamiliar to the learner. METHODS: Using preoperative computed tomography data, the authors produced an accurately sized, three-dimensional (3D) printed model of the congenital craniofacial anatomy of patients treated by the same attending surgeon-PGY4 resident surgeon pair over the course of a 6-month rotation. A preoperative stepwise surgical plan was written by the attending and resident, and the plan was marked on the 3D model by the attending and resident separately. The written and marked plans were measured for accuracy and time to completion. The resident surgeon's applicable milestone levels were assessed. RESULTS: Seven congenital craniofacial anomalies met criteria for inclusion: 4 craniosynostosis cases, 2 mandibular distractions, and 1 LeFort I distraction. The number of inaccuracies of the written plan improved from 5 to 0 for sagittal synostosis and 4 to 0 for mandibular distraction. The time to complete the written plan decreased by 22% for sagittal synostosis and 45% for mandibular distraction. The number of inaccuracies of the marked plan decreased from 5 to 0 for sagittal synostosis and 2 to 0 for mandibular distraction. Time to completion of the marked plan decreased by 76% for sagittal synostosis and 50% for mandibular distraction. Milestone scores increased an average of 1.875 levels. CONCLUSION: Three-dimensional printed craniofacial models are a positive addition to resident training and have been objectively quantified to improve the accuracy and time to completion of the surgical plan as well as progression in the plastic surgery milestones.

Fenestration Improves Acellular Dermal Matrix Biointegration: An Investigation of Revascularization with Photoacoustic Microscopy.

BACKGROUND: Acellular dermal matrices have revolutionized alloplastic breast reconstruction. Furthering our knowledge of their biointegration will allow for improved design of these biomaterials. The ideal acellular dermal matrix for breast reconstruction would provide durable soft-tissue augmentation while undergoing rapid biointegration to promote physiologic elasticity and reduced infectious complications. The inclusion of fenestrations in their design is thought to promote the process of biointegration; however, the mechanisms underlying this theory have not been evaluated. METHODS: Biointegration of standard and fenestrated acellular dermal matrices was assessed with serial photoacoustic microscopic imaging, in a murine dorsal skinfold window chamber model specifically designed to recapitulate the microenvironment of acellular dermal matrix-assisted alloplastic breast reconstruction. Photoacoustic microscopy allows for a serial, real-time, noninvasive assessment of hemoglobin content and oxygen saturation in living tissues, generating high-resolution, three-dimensional maps of the nascent microvasculature within acellular dermal matrices. Confirmatory histologic and immunohistochemical assessments were performed at the terminal time point. RESULTS: Fenestrated acellular dermal matrices demonstrated increased fibroblast and macrophage lineage host cell infiltration, greater mean percentage surface area vascular penetration (21 percent versus 11 percent; p = 0.08), and greater mean oxygen saturation (13.5 percent versus 6.9 percent; p < 0.05) than nonfenestrated matrices by 2 weeks after implantation. By 21 days, host cells had progressed nearly 1 mm within the acellular dermal matrix fenestrations, resulting in significantly more vascularity across the top of the fenestrated matrix (3.8 vessels per high-power field versus 0.07 vessels per high-power field; p < 0.05). CONCLUSIONS: Inclusion of fenestrations in acellular dermal matrices improves the recellularization and revascularization that are crucial to biointegration of these materials. Future studies will investigate the optimal distance between fenestrations.

Treatment With Topical Deferoxamine Improves Cutaneous Vascularity and Tissue Pliability in an Irradiated Animal Model of Tissue Expander-Based Breast Reconstruction.

PURPOSE: Postmastectomy radiation therapy is an important component of the multimodality approach to later-stage breast cancers. Unfortunately, despite its proven survival benefits, postmastectomy radiation therapy is deleterious to the skin and soft tissue, causing increased complications and worse aesthetic outcomes after breast reconstruction.There is currently no effective pharmaceutical agent to mitigate the soft tissue fibrosis and hypovascularity associated with soft tissue radiation. We hypothesized that a novel topical formulation of deferoxamine (DFX) will result in improved cutaneous vascularity and soft tissue pliability in an animal model of irradiated tissue expander-based breast reconstruction. METHODS: This study consisted of 16 hairless rats divided into 4 equal groups: a control group (expander only), a tissue expanded and irradiated group, a tissue expanded + DFX group, and a tissue expanded/irradiated/DFX group. A novel topical formulation of DFX consisted of reconstituted drug dissolved in agents designed to enhance dermal penetrance. Vessels per high-power field (vHPF) were quantified histologically; micro-computed tomography angiography was used to assess vessel volume fraction (VVF) and vessel length density. RESULTS: Irradiated skin had less vascularity compared with control (3.81 vHPF vs 8.25 vHPF, P = 0.03; 0.79% VVF vs 1.53% VVF, P = 0.06). Treatment of irradiated skin with topical DFX reversed these effects, resulting in vascular findings similar to the control group histologically (7.94 vHPF vs 8.25 HPF, P = 0.985) and via micro-computed tomography angiography (1.05% VVF vs 1.53% VVF, P = 0.272). Similarly, radiation resulted in less volume expansion compared with controls (0.72 vs 0.8 mL, P = 0.04), whereas treatment with topical DFX reversed this effect, allowing for an expansion volume similar to the control group (0.81 vs 0.80 mL, P = 0.999). CONCLUSIONS: In an animal model of irradiated tissue expander-based breast reconstruction, treatment with topical DFX improved the cutaneous vascularity and tissue pliability, resulting in vascular density and final tissue expansion volumes similar to those found in the nonirradiated control group. Topical DFX may be an effective agent for the treatment of soft tissue radiation injury; future studies are indicated to further characterize this novel drug formulation.

Evaluating a Variable Porosity Wound Dressing With Anti-Scar Properties in a Porcine Model of Wound Healing.

Introduction: New treatments that promote wound healing while preventing scar formation are needed. One option in topical wound healing is the use of temporary dressings that allow the natural healing process with minimal scar formation. Methods: We evaluated the temporary wound dressings PermeaDerm C, and a PermeaDerm C derivative coated with the anti-scarring agent, salinomycin (PermeaDerm D) in a pig model of wound healing to show the efficacy of these wound dressings in vivo. Results: Porcine fibroblasts grow well in the presence of PermeaDerm C or PermeaDerm A, and salinomycin reduces excessive myofibroblast formation in porcine fibroblasts in vitro. In vivo, wounds treated with PermeaDerm C and PermeaDerm A did not show abnormal or unwanted healing patterns up to 8 weeks post-wound formation. Wounds covered with either PermeaDerm C or PermeaDerm A showed a more mature wound-healing phenotype than the control wounds. Conclusions: PermeaDerm C and PermeaDerm A allowed wound healing, revealing the potential of both PermeaDerm C and PermeaDerm A to promote effective healing while preventing excessive scar formation.

In Vitro Characterization of Variable Porosity Wound Dressing With Anti-Scar Properties.

Introduction: New options are needed to improve wound healing while preventing excessive scar formation. Temporary primary dressings are important options in topical wound management that allow the natural healing process. Methods: We evaluated a novel primary dressing consisting of a biosynthetic, variable porosity, matrix-containing gelatin and Aloe Vera extract and a derivative dressing coated with the anti-scarring agent salinomycin for their ability to promote cell growth, reduce myofibroblast formation, and regulate cytokine production. In addition, salinomycin-coated primary dressings were tested for antimicrobial activity. Results: Both primary wound dressings permitted cell growth and attenuated TGFß-induced scar-forming myofibroblast formation. The primary wound dressings also reduced IL-6 production by 50%, IL-8 by 20%, MCP-1 by 75%, and GRO by 60% in human mesenchymal stem cells treated with TGFß. Salinomycin coating of the dressing showed antimicrobial activity by preventing Staphylococcus aureus growth. Conclusions: Both primary wound dressings support the growth of human fibroblasts and stem cells, as well as reduce inflammatory cytokine production, demonstrating their potential to serve as temporary wound dressings.