Adipose Tissue Therapeutics for Scar Rehabilitation after Thermal Injury

Background: Burn injuries are common and in the long term can lead to hypertrophic or keloid scars, pain and pruritus, limited mobility across joints, and disfigurement. Numerous reports suggest adipose derived tissues, including adipose derived stem cells (ADSCs) and processed lipoaspirate, can improve acutely healing wounds from a variety of etiologies including excisional, thermal, and radiation injuries by both secretion of growth factors and direct differentiation. There are many options for scar treatment, including laser therapy, silicone sheets, steroid injection, and even skin grafting however these techniques either lack optimal efficacy or involve significant cost and morbidity. Clinical case series suggest a beneficial effect of adipose tissues in improving scarred tissues, however this phenomenon has not been extensively studied in animal models especially in a thermal scar model. Objectives: (1) Determine if adipose tissue can accelerate and improve scar remodeling subacutely after acute wound healing has occurred. (2) Determine if the effect is related to adipose derived stem cells or other components of lipoaspirate. Methods: 50 CD1 nu/nu athymic mice received a standardized 70°C 10 second burn with a brass rod to the dorsal skin. Digital photographs and hyperspectral images were taken immediately following injury and serially over the study’s entirety. Burned skin reliably progressed through normal stages of wound healing to a scarred and granulating state. At six weeks post-burn animals received subcutaneous injection immediately beneath the scar with fresh human lipoaspirate (n=10), high dose hADSCs in matrigel (n=10), low dose hADSCs in matrigel (n=10), matrigel control (n=10), or were not injected (n=10). At 4 weeks post-injection (10 weeks post-burn) animals were sacrificed and tissue samples were harvested for histological molecular analysis. Results: Oxygenation and perfusion profiles from hyperspectral imaging and scar wound area correlated between groups suggesting methodological consistency of burns prior to any intervention. Oxygenated hemoglobin at 10 weeks in scars treated with lipoaspirate increased significantly more compared to 6-week pre-treatment baseline than all other groups (1.57x vs. 0.85x, p Conclusion: A consistent model of burn injury and scar maturation is described. Preliminary HSI and scar area data suggest scar improvement in lipoaspirate treated scars compared to ADSCs and controls

Lipoaspirate and Adipose Stem Cells as Potential Therapeutics for Chronic Scars

Introduction: Burn injuries can lead to hypertrophic or keloid scars, causing pain and long lasting mobility issues. Current therapies are often unsatisfactory, costly, or morbid. Prior studies suggest adipose derived stem cells (ADSCs) and lipoaspirate can improve scar outcomes of acute thermal wounds. Clinical reports suggest lipoaspirate and ADSCs can improve chronic burn scar remodeling. However, this has not been extensively studied in animal models. We sought to determine if adipose tissue can improve chronic scar remodeling and to compare the effects of ADSCs and processed lipoaspirate. Methods: 50 CD1 nu/nu athymic mice received a standardized deep partial-thickness thermal burn. Scars matured for 6 weeks. Photographs and perfusion measurements by hyperspectral imaging (HSI) were taken over the entire study. Lipoaspirate and ADSCs (SVF and ex-vivo culture with flow cytometry confirmation) were obtained from a discarded human pannus specimen. After 6 weeks, animals received a 0.6cc subcutaneous graft beneath the scar of either: human lipoaspirate processed with the Coleman technique, high-dose (106) hADSCs in Matrigel, low-dose (104) hADSCs in Matrigel, Matrigel only, or not injected (n=10 per group). At 10 weeks, animals were sacrificed and scar tissue was harvested for histological and molecular analysis. Results: HSI oxygenated hemoglobin values in lipoaspirate treated scars increased significantly more compared to 6-week pre-treatment baseline than all other groups (p \u3c 0.05). Planimetry analysis showed reduction in wound area in lipoaspirate treated mice compared to control groups (p \u3c 0.01). Blood vessel density quantification on Masson’s trichrome stains suggests increased density in lipoaspirate treated scars versus controls (p \u3c 0.01). Conclusion: HSI, blood vessel density, and scar analysis suggest improvement in lipoaspirate treated scars compared to controls. Preliminary molecular data offers some insight to this trend. No effect was seen with ADSCs at either concentration at the analyzed timepoints. Molecular analyses are ongoing to investigate cellular mechanisms in regulating scar remodeling

An Old Idea Revisited: Reflections on the Role of Aesthetic Surgery in Behavioral and Social Change

Although the notion that an individual’s morality can be changed from bad to good solely with a procedure that improves physical appearance is controversial, the relationship between appearance and behavior is complex and pertinent to an individual’s psychology and quality of life. Where plastic surgery comes into play, as either treatment or adjuvant therapy, remains to be determined

Anesthetic and surgical considerations in osteogenesis imperfecta: A case report of mandible fracture management

Background: Osteogenesis imperfecta (OI) is a rare metabolic bone disorder in which collagen production is impaired. Patients have brittle bones that are prone to fracture with minor trauma. Whereas most of the fractures occur in the spine and extremities, fractures of the craniofacial bones are less common.Methods: This report describes the management of a 14-year-old boy with OI type 1 who sustained mandible fractures from an assault. Management consisted of open reduction and internal fixation of the parasymphyseal and angle fractures and closed reduction and mandibulomaxillary fixation of the subcondylar fracture.Results: Surgery resulted in return of premorbid occlusion and good jaw function. Removal of plates and screws was performed 10 months later without incident.Conclusions: This case report discusses the unique anesthetic, surgical, and postoperative considerations for managing mandible fractures in patients with OI

Alternatively Activated M2 Macrophages Improve Autologous Fat Graft Survival in a Mouse Model through Induction of Angiogenesis

Comment on: Alternatively activated M2 macrophages improve autologous Fat Graft survival in a mouse model through induction of angiogenesis. [Plast Reconstr Surg. 2015

Hyperspectral Imaging Provides Early Prediction of Random Axial Flap Necrosis in a Preclinical Model

BACKGROUND: Necrosis remains a significant complication in cutaneous flap procedures. Monitoring, and ideally prediction, of vascular compromise in the early postoperative period may allow surgeons to limit the impact of complications by prompt intervention. Hyperspectral imaging could be a reliable, effective, and noninvasive method for predicting flap survival postoperatively. In this preclinical study, the authors demonstrate that hyperspectral imaging is able to correlate early skin perfusion changes and ultimate flap survival in a preclinical model. METHODS: Thirty-one hairless, immunocompetent, adult male mice were used. Random pattern dorsal skin flaps were elevated and sutured back into place with a silicone barrier. Hyperspectral imaging and digital images were obtained 30 minutes, 24 hours, or 72 hours after flap elevation and before sacrifice on postoperative day 7. RESULTS: Areas of high deoxygenated hemoglobin change (124; 95 percent CI, 118 to 129) seen at 30 minutes after surgery were associated with greater than 50 percent flap necrosis at postoperative day 7. Areas demarcated by high deoxygenated hemoglobin at 30 minutes postoperatively had a statistically significant correlation with areas of macroscopic necrosis on postoperative day 7. Analysis of images obtained at 24 and 72 hours did not show similar changes. CONCLUSIONS: These findings suggest that early changes in deoxygenated hemoglobin seen with hyperspectral imaging may predict the region and extent of flap necrosis. Further clinical studies are needed to determine whether hyperspectral imaging is applicable to the clinical setting

External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site

BACKGROUND: External volume expansion prepares recipient sites to improve outcomes of fat grafting. For patients receiving radiotherapy after mastectomy, results with external volume expansion vary, and the relationship between radiotherapy and expansion remains unexplored. Thus, the authors developed a new translational model to investigate the effects in chronic skin fibrosis after radiation exposure. METHODS: Twenty-four SKH1-E mice received 50 Gy of beta-radiation to each flank and were monitored until fibrosis developed (8 weeks). External volume expansion was then applied at -25 mmHg to one side for 6 hours for 5 days. The opposite side served as the control. Perfusion changes were assessed with hyperspectral imaging. Mice were euthanized at 5 (n = 12) and 15 days (n = 12) after the last expansion application. Tissue samples were analyzed with immunohistochemistry for CD31 and Ki67, Masson trichrome for skin thickness, and picrosirius red to analyze collagen composition. RESULTS: All animals developed skin fibrosis 8 weeks after radiotherapy and became hypoperfused based on hyperspectral imaging. Expansion induced edema on treated sides after stimulation. Perfusion was decreased by 13 percent on the expansion side (p \u3c 0.001) compared with the control side for 5 days after stimulation. Perfusion returned to control-side levels by day 15. Dermal vasculature increased 38 percent by day 15 (p \u3c 0.01) in expansion versus control. No difference was found in collagen composition. CONCLUSIONS: External volume expansion temporarily reduces perfusion, likely because of transient ischemia or edema. Together with mechanotransduction, these effects encourage a proangiogenic and proliferative environment in fibrotic tissue after radiotherapy in the authors\u27 mouse model. Further studies are needed to assess these changes in fat graft retention

Increasing Fat Graft Retention in Irradiated Tissue after Preconditioning with External Volume Expansion

BACKGROUND: Fat grafting is an adjuvant that may improve the quality of radiation-damaged tissue. However, fat grafting for volume restoration in irradiated sites may be less effective because of a poorly vascularized fibrotic recipient bed. External volume expansion has emerged as a potential technique to prepare the recipient sites for improved survival of grafted fat. The authors previously demonstrated increased vasculature with external volume expansion stimulation of irradiated tissues. The authors now hypothesize that external volume expansion\u27s improvements in recipient-site vascularity will increase the volume retention and quality of fat grafts in fibrotic irradiated sites. METHODS: Athymic mice were irradiated until development of chronic radiation injury. Then, the irradiated site was stimulated by external volume expansion (external volume expansion group), followed by subcutaneous fat grafting. Grafts in an irradiated site without external volume expansion stimulation (irradiated control group) and grafts in a healthy nonirradiated (nonirradiated control group) site were used as controls. All grafts were monitored for 8 weeks and evaluated both histologically and by micro-computed tomography for analysis of volume retention. RESULTS: Hyperspectral imaging confirmed a 25 percent decrease in vascularity of irradiated tissue (irradiated control group) compared with nonirradiated tissue (nonirradiated control group). Grafts in the irradiated control group retained 11 percent less volume than grafts in the nonirradiated control group. The experimental external volume expansion group achieved a 20 percent (p = 0.01) increase in retained graft volume compared with the irradiated control group. CONCLUSIONS: External volume expansion stimulation can mitigate the effects of irradiation at the recipient site and in turn help preserve fat graft volume retention. Possible mechanisms include increased vascularity, adipogenic conversion, and increased compliance of a fibrotic recipient site

Etonogestrel concentrations among contraceptive implant users in Botswana using and not using dolutegravir-based antiretroviral therapy

Objectives: To evaluate whether etonogestrel concentrations are reduced to a level that could potentially reduce contraceptive efficacy when the etonogestrel contraceptive implant is used concomitantly with dolutegravir-based antiretroviral therapy (ART). Study Design: We conducted a non-randomized, open-label, cross-sectional pharmacokinetic study among women using single-rod etonogestrel contraceptive implants in Botswana. We compared plasma etonogestrel concentrations, sampled at a single time-point between 3 and 12 months from implant insertion, among implant users living with HIV and receiving dolutegravir-based ART with HIV-negative implant users. We also assessed concentrations among implant users living with HIV and receiving efavirenz-based ART. We compared geometric mean etonogestrel concentrations analyzing data from 142 participants: 97 HIV-negative, 30 using dolutegravir, and 15 using efavirenz. Results: The groups were similar. Duration of implant use was between 3 and 12 months (median=5). Geometric mean etonogestrel plasma concentrations and 90% confidence intervals of the mean were 227.5(212.4-243.8), 289.6(251.8-333.0) and 76.4(63.9-91.4) pg/mL among the HIV-negative, dolutegravir- and efavirenz-based ART groups, respectively. All women in the HIV-negative and dolutegravir-based ART groups had etonogestrel concentrations above 90pg/mL; 9/15 women (60%) using efavirenz-based ART had concentrations below 90 pg/mL. On average, etonogestrel levels were lower among individuals who had implants inserted for longer durations. Conclusions: Implant users receiving dolutegravir-based ART had a higher mean etonogestrel concentration compared to HIV-negative women, and none had etonogestrel concentrations below the posited threshold for ovulation suppression. In contrast, women in the efavirenz-group had much lower etonogestrel concentrations. Overall, these data provide evidence that the etonogestrel implant may be effectively combined with dolutegravir-based ART regimens