Frontline Reporting from the Epicenter of a Global Pandemic: A Survey of the Impact of COVID-19 on Plastic Surgery Training in New York and New Jersey.

BACKGROUND: Since the first documented case of coronavirus disease of 2019 (COVID-19), the greater New York City area quickly became the epicenter of the global pandemic, with over 500,000 cases and 50,000 deaths. This unprecedented crisis affected all aspects of health care, including plastic surgery residency training. The purpose of this study was to understand the specific impact of the COVID-19 pandemic on plastic surgery residencies. METHODS: A survey of all plastic surgery residency training programs in the greater New York City area was conducted. The impact to training during the peak months of infection (March and April of 2020) was evaluated using resident education as measured by case numbers, need for redeployment, and staff wellness as primary outcome variables. RESULTS: A total of 11 programs were identified in the region, and seven programs completed the survey, with a response rate 63.6 percent. When comparing productivity in March and April of 2019 to March and April of 2020, a total decrease in surgical volume of 64.8 percent (range, 19.7 to 84.8 percent) and an average of 940 (range, 50 to 1287) cancelled clinic visits per month were observed. These decreases directly correlated with the local county's COVID-19 incidence rates (p = 0.70). A total of 83 percent of programs required redeployment to areas of need, and correlation between local incidence of COVID-19 and the percentage of residents redeployed to non-plastic surgical clinical environments by a given program (ρ = 0.97) was observed. CONCLUSION: As the first COVID-19 wave passes the greater New York area and spreads to the rest of the country, the authors hope their experience will shed light on the effects of the ongoing COVID-19 pandemic, and inform other programs on what to expect and how they can try and prepare for future public health crises.

Treatment of Upper Extremity Lymphedema following Chemotherapy and Radiation for Head and Neck Cancer.

In the industrialized world, the most common cause of secondary lymphedema is iatrogenic. The inciting event is generally a combination of lymph node resection, chemotherapy, and radiation therapy. Although a regional nodal dissection is often the primary risk factor, lymphedema can also result from sentinel node dissections, or as in the case presented without any surgical resection. Here, we present a unique case of upper extremity lymphedema resulting from definitive chemoradiation for squamous cell carcinoma of the head and neck. The patient was treated using a combined approach with a lymphaticovenular anastomosis and a free vascularized inguinal lymph node transfer.

The Latissimus Dorsi Myocutaneous Flap Is a Safe and Effective Method of Partial Breast Reconstruction in the Setting of Breast-Conserving Therapy.

BACKGROUND: Reconstruction of partial breast defects in low-volume, nonptotic breasts can be challenging. The authors hypothesized that use of the latissimus dorsi flap in partial breast reconstruction is safe and associated with low complication and high patient satisfaction rates. METHODS: All patients who underwent breast-conserving therapy and latissimus dorsi flap reconstruction from January 1, 2006, to December 31, 2016, were identified in a prospectively maintained database. Patient demographics, tumor characteristics, and complications were recorded. Patient-reported outcomes were assessed with the BREAST-Q breast-conserving therapy module. A group of plastic surgeons and laypersons used a five-point Likert scale to evaluate aesthetic outcomes in representative patients. RESULTS: Forty-seven patients met the inclusion criteria. Median follow-up was 5.4 years. Most patients (93.6 percent) underwent immediate reconstruction. The mean resection volume was 219.5 cc (range, 70 to 877 cc). The overall complication rate was 8.5 percent. Grade 2 or 3 ptosis (OR, 1.21; 95 percent CI, 1.0 to 1.46; p = 0.03), smoking (OR, 13.1; 95 percent CI, 1.2 to 143.2; p = 0.03), and multicentric tumor (OR, 1.23; 95 percent CI, 1.04 to 1.64; p = 0.02) were associated with a higher complication rate. Ductal carcinoma in situ was associated with reoperation for positive margins (OR, 14.4; 95 percent CI, 2.1 to 100; p = 0.009). Of particular interest, patient-reported outcomes were favorable, with the highest rated domains being Satisfaction with Breasts (61; interquartile range, 37 to 77), Psychosocial Well-being (87; interquartile range, 63 to 100), and Physical Well-being (87; interquartile range, 81 to 100). The median aesthetic score was 4 (of 5). CONCLUSIONS: This is the first study to date using the BREAST-Q to assess patient-reported outcomes associated with the latissimus dorsi flap for partial breast reconstruction. The flap is safe and effective for reconstruction in the setting of breast-conserving therapy, providing aesthetically pleasing results with high patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Improving Senescent Wound Healing With Local and Systemic Therapies.

The population is aging, and the prevalence of chronic wounds is increasing. Because neovascularization is essential for tissue repair and both local and systemic factors affect new blood vessel formation, we hypothesize that altering either pathway would reciprocally enhance wound healing in the aged. To test this hypothesis, p53 was locally suppressed and endothelial progenitor cells (EPCs) were systemically mobilized in a murine model of senescent wound healing.Bilateral 6-mm full-thickness stented wounds were made on the dorsum of Zmpste24 mice. Animals received weekly topical p53 small interfering RNA (siRNA) (n = 25), weekly topical nonsense siRNA (n = 25), daily subcutaneous AMD3100 injections (n = 25), or daily subcutaneous saline injections (n = 25). Wounds were photographically assessed and harvested for reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunostaining over 40 days. Circulating EPC levels were measured using fluorescence-activated cell sorting analysis.Local p53 siRNA significantly improved Zmpste24 wound healing (18 ± 2 vs 40 ± 3 days; P ≤ 0.0001). p53 siRNA significantly increased local provasculogenic factors (hypoxia-inducible factor 1 α, stromal cell-derived factor 1 α, and vascular endothelial growth factor; P ≤ 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P ≤ 0.05). Local p53 siRNA also significantly increased the number of circulating EPCs (8 ± 0.2% vs 2.6 ± 0.1%; P ≤ 0.0001). AMD3100 treatment also significantly improved wound healing (20 ± 2 vs 40 ± 3 days; P ≤ 0.0001) and increased EPCs mobilization (7.8 ± 0.4% vs 2.6 ± 0.1%; P ≤ 0.0001). In addition, systemic AMD3100 increased local provasculogenic factors (hypoxia-inducible factor 1 α, stromal cell-derived factor 1 α, and vascular endothelial growth factor; P ≤ 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P ≤ 0.05). Both treatments significantly increased the number of blood vessels in the wound bed (P ≤ 0.0001).The marked delay in Zmpste24 wound healing is significantly improved by local (p53 siRNA) and systemic (AMD3100) treatments. The resulting decrease in proapoptotic factors and increase in provasculogenic factors in the wound bed as well as the increased level of circulating EPCs appear to reverse age-related wound healing impairment by enhancing wound neovascularization.

The ideal ear position in Caucasian females.

PURPOSE: Ear position contributes significantly to facial appearance. However, while objective measurements remain the foundation for esthetic evaluations, little is known about how an ear should ideally be positioned regarding its rotational axis. This study aimed to further evaluate whether there exists a universally applicable ideal ear axis, and how sociodemographic factors impact such preferences. MATERIALS AND METHODS: An interactive online survey was designed, enabling participants to change the axis of a female model's ear in terms of its forward and backward rotation. The questionnaire was sent out internationally to plastic surgeons and the general public. Demographic data were collected and analysis of variance was used to investigate respective preferences. RESULTS: A total of 1016 responses from 35 different countries (response rate: 18.5%) were gathered. Overall, 60% of survey takers chose the minus 10 or 5° angles to be most attractive. Significant differences were found regarding sex, ethnicity, country of residence, profession and respective ear axis preferences. CONCLUSION: Across multiple countries and ethnicities, an ear position in slight reclination of minus 5-10° is considered most pleasing in Caucasian females. However, sociodemographic factors significantly impact individual ear axis preferences and should be taken into consideration when performing reconstructive ear surgery.

The Ideal Buttock Size: A Sociodemographic Morphometric Evaluation.

BACKGROUND: Perception of beauty is influenced by geographic, ethnic, cultural, and demographic factors. However, objective measurements remain the foundation for aesthetic evaluations. In the quest to better define the "ideal" female buttock, this study assumes interdependence among variables such as country of residence, sex, age, occupation, and aesthetic perception, yielding a waist-to-hip ratio that appears most pleasing across most cultures and geographic locations. METHODS: An online survey was designed. Modifiable ranges of buttock sizes were achieved by means of digital alteration, enabling participants to interactively change the size and waist-to-hip ratio of a single model's buttocks. The questionnaire was translated into multiple languages and sent to more than 9000 plastic surgeons and to the general public worldwide. Demographic data were collected, and analysis of variance was used to elucidate buttock shape preferences. RESULTS: A total of 1032 responses were gathered from over 40 different countries. Significant differences regarding preferences for buttock size were identified across the respondents. Overall, 404 of 1032 of survey takers (39 percent) chose the 0.7 waist-to-hip ratio to be their ideal. Significant relationships were distilled between sex, age, self-reported ethnicity, plastic surgeons' country of residence, and ethnic background. For example, surgeons in Latin America preferred the largest buttocks, followed by surgeons in Asia, North America, and Europe, with non-Caucasians preferring larger buttocks than Caucasians. CONCLUSION: There seems to exist a global consensus regarding the ideal waist-to-hip ratio; however, multiple other factors impact the aesthetic perception of the buttocks significantly.

The current preferred female lip ratio.

BACKGROUND: Perception of beauty is influenced by the individual's demographic background and characteristics. However, objective measurements and ratios remain the foundation for aesthetic evaluations. This study aimed to elucidate if there exists a universally applicable ideal upper to lower lip ratio. METHODS: An interactive online survey was designed. Modifiable ranges of lip ratios were achieved via digital alteration, enabling participants to change the ratio of a single female model's lips. The questionnaire was translated into multiple languages and sent to more than 9000 plastic surgeons and the general public worldwide. Demographic data were collected and analysis of variance was used to investigate respective lip ratio preferences. RESULTS: A total of 1011 responses from 35 different countries (response rate of 14%) was gathered. The majority of survey takers (60%) chose the 1.0:1.0 lip ratio as most attractive. No differences were found in respect to lip ratio preference and the self-reported ethnicity. However, interesting preferences prevailed when analyzing the subgroups regarding lower lip size. CONCLUSION: Age, gender, country of residence, and profession significantly impact individual upper to lower lip ratio preferences. However, a 1.0:1.0 lip ratio can apparently be considered most pleasing in females.

Early Distraction for Mild to Moderate Unilateral Craniofacial Microsomia: Long-Term Follow-Up, Outcomes, and Recommendations.

BACKGROUND: There is controversy regarding the treatment of young patients with unilateral craniofacial microsomia and moderate dysmorphism. The relative indication for mandibular distraction in such patients poses several questions: Is it deleterious in the context of craniofacial growth and appearance? This study was designed to address these questions. METHODS: A retrospective review of patients undergoing mandibular distraction by a single surgeon between 1989 and 2010 was conducted. Patients with "moderate" unilateral craniofacial microsomia (as defined by Pruzansky type I or IIa mandibles) and follow-up until craniofacial skeletal maturity were included for analysis. Patients were divided into two cohorts: satisfactory and unsatisfactory results based on photographic aesthetic evaluation by independent blinded observers at the initial presentation and at the age of skeletal maturity. Clinical variables were analyzed to detect predictors for satisfactory distraction. RESULTS: Nineteen patients were included for analysis. The average age at distraction was 68.2 months and the average age at follow-up was 19.55 years. Thirteen patients (68.4 percent) had Pruzansky type IIA and six patients (31.6 percent) had Pruzansky type I mandibles. Twelve patients (63.2 percent) had satisfactory outcomes, whereas seven patients (36.8 percent) had unsatisfactory outcomes. Comparing the two cohorts, patients with satisfactory outcomes had distraction at an earlier age (56.4 months versus 89.8 months; p = 0.07) and a greater percentage overcorrection from craniofacial midline (41.7 percent versus 1.8 percent; p = 0.003). CONCLUSION: Mandibular distraction is successful in patients with mild to moderate dysmorphism, provided that there is a comprehensive clinical program emphasizing adequate mandibular bone stock, proper vector selection, planned overcorrection, and comprehensive orthodontic management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Lip Attractiveness: A Cross-Cultural Analysis.

Background: Perception of beauty is influenced by the individual's geographic, ethnic, cultural, and demographic background. However, objective measurements remain the foundation for aesthetic evaluations. In the quest for to better define "ideal" lip characteristics, this study assumes interdependence between variables such as country of residence, sex, age, occupation, and aesthetic perception. Objectives: This study will increase surgeons' awareness with respect to different lip size preferences. The provided information might enhance and clarify communication among plastic surgeons and aid to put often quoted "ideal proportions" in context. Methods: An online survey was designed. Modifiable ranges of lip fullness were achieved via digital alteration, enabling participants to interactively change the shape of a single model's lips. The questionnaire was sent to more than 9000 plastic surgeons and laypeople worldwide. Demographic data were collected and analysis of variance was used to elucidate lip shape preferences. Results: A total of 1011 responses (14% response rate) from 35 different countries were gathered. Significant differences regarding lip fullness were identified. Surgeons who practice in Asia or non-Caucasian surgeons prefer larger lips, while those in Europe and Caucasians prefer smaller lips. Lastly, laypersons living in Asia prefer the smallest lips. Conclusions: Country of residence, ethnic background, and profession significantly impact individual lip shape preferences. These findings have implications for patients and surgeons, because differences in aesthetics' preferences can lead to dissatisfaction of patients and surgeons alike. In our increasingly global environment, cultural differences and international variability must be considered when defining new aesthetic techniques, treating patients, and reporting outcomes.

Added Qualifications in Microsurgery: Consideration for Subspecialty Certification in Microvascular Surgery in Europe.

Background While implementation of subspecializations may increase expertise in a certain area of treatment, there also exist downsides. Aim of this study was, across several disciplines, to find out if the technique of microsurgery warrants the introduction of a "Certificate of Added Qualifications (CAQ) in microsurgery." Methods An anonymous, web-based survey was administered to directors of microsurgical departments in Europe (n = 205). Respondents were asked, among other questions, whether they had completed a 12-month microvascular surgery fellowship and whether they believed a CAQ in microvascular surgery should be instituted. Results The response rate was 57%, and 33% of the respondents had completed a 12-month microvascular surgery fellowship.A total of 61% of all surgeons supported a CAQ in microsurgery. Answers ranged from 47% of support to 100% of support, depending on the countries surveyed. Discussion This is one of the few reports to evaluate the potential role of subspecialty certification of microvascular surgery across several European countries. The data demonstrate that the majority of directors of microsurgical departments support such a certificate. There was significantly greater support for a CAQ in microsurgery among those who have completed a formal microvascular surgery fellowship themselves. Conclusion This study supports the notion that further discussion and consideration of subspecialty certification in microvascular surgery appears necessary. There are multiple concerns surrounding this issue. Similar to the evolution of hand surgery certification, an exploratory committee of executive members of the respective medical boards and official societies may be warranted.

Postoperative Expansion is not a Primary Cause of Infection in Immediate Breast Reconstruction with Tissue Expanders.

Perioperative infection is the most common and dreaded complication associated with tissue expander (TE) breast reconstruction. Historically, the expansion period was thought to be the time of greatest hazard to the implant. However, recent institutional observations suggest infectious complications occur prior to expansion. This investigation, therefore, was conducted to determine the timing of infectious complications associated with two-stage TE breast reconstructions. Following IRB approval, a retrospective review of all consecutive two-stage immediate TE breast reconstructions at a single institution from November 2007 to November 2011 was conducted. Reconstructions were then divided into two cohorts: those suffering infectious complications and those that did not. Infectious complications including minor cellulitis, major cellulitis, abscess drainage, and explantation were identified. Various operative and patient variables were evaluated in comparison. Eight hundred ninety immediate two-stage TE breast reconstructions met inclusion criteria. Patients suffering infection were older (55.4 years versus 49.3 years; p < 0.001), and more likely to have therapeutic mastectomy (94% versus 61%; p < 0.0001), the use of acellular dermal matrix (ADM; 72.5% versus 54.9%; p = 0.001), and greater initial TE fill (448.6 mL versus 404.7 mL; p = 0.0078). The average time to developing of infectious symptoms was 29.6 days (range 9-142 days), with 94.6% (n = 87) of infections prior to the start of expansion. Perioperative infections in immediate two-stage TE to implant breast reconstructions are significant and occur mostly prior to the start of expansion. Thus, challenging the conventional wisdom that instrumentation during expander filling as the primary cause of implant infections. Possible etiologic factors include greater age, therapeutic mastectomy versus prophylactic mastectomy, larger initial TE fill, and the use of ADM.

Unilateral Craniofacial Microsomia: Unrecognized Cause of Pediatric Obstructive Sleep Apnea.

Bilateral craniofacial microsomia causes obstructive sleep apnea (OSA). We hypothesize that unilateral craniofacial microsomia (UCFM) is an underappreciated cause of OSA. The records of all pediatric UCFM patients from 1990 to 2010 were reviewed; only complete records were included in the study. UCFM patients with OSA (apnea hypopnea index >1/hr) were compared to UCFM patients without OSA. Univariate and multivariate Fisher and χ(2) tests were performed. Of the 62 UCFM patients, 7 (11.3%) had OSA. All OSA patients had Pruzansky IIB or III mandibles. OSA patients presented with snoring (71.4%), failure to thrive (FTT) (57.1%), and chronic respiratory infections (42.8%). Snoring (P < 0.001), Goldenhar syndrome (P = 0.001), and FTT (P = 0.004) were significantly associated with OSA, but race, obesity, clefts, respiratory anomalies, adenotonsillar hypertrophy, and laterality were not. The prevalence of OSA in UCFM patients is up to 10 times greater than in the general population. Snoring, Goldenhar syndrome, and FTT are significantly associated with the presence of OSA.

Acellular dermal matrix-based gene therapy augments graft incorporation.

BACKGROUND: Acellular dermal matrix (ADM) is widely used for structural or dermal replacement purposes. Given its innate biocompatibility and its potential to vascularize, we explored the possibility of ADM to function as a small interfering RNA (siRNA) delivery system. Specifically, we sought to improve ADM vascularization by siRNA-mediated inhibition of prolyl hydroxylase domain-2 (PHD2), a cytoplasmic protein that regulates hypoxia inducible factor-1α, and improve neovascularization. MATERIALS AND METHODS: Fluorescently labeled siRNA was used to rehydrate thin implantable ADM. Pharmacokinetic release of siRNA was determined. Twelve millimeter sections of ADM reconstituted with PHD2 siRNA (nonsense siRNA as control) and applied to dorsal wounds of 40 FVB mice. Grafts were sewn in, bolstered, and covered with occlusive dressings. Photographs were taken at 0, 7, and 14 d. Wounds were harvested at 7 and 14 d and analyzed (messenger RNA, protein, histology, and immunohistochemistry). RESULTS: Release kinetics was first-order with 80% release by 12 h. By day 14, PHD2-containing ADM appeared viable and adherent, whereas controls appeared nonviable and nonadherent. Real-time reverse transcription-polymerase chain reaction demonstrated near-complete knockdown of PHD2, whereas vascular endothelial growth factor and FGF-2 were increased 2.3- and 4.7-fold. On enzyme-linked immunosorbent assay, vascular endothelial growth factor was increased more than fourfold and stromal cell-derived factor doubled. Histology demonstrated improved graft incorporation in treated groups. Immunohistochemical demonstrated increased vascularity measured by CD31 staining and increased new cell proliferation by denser proliferating cell nuclear antigen staining in treated versus controls. CONCLUSIONS: We concluded that ADM is an effective matrix for local delivery of siRNA. Strategies to improve the matrix and/or genetically alter the local tissue environment can be envisioned.

Endogenous cell therapy improves bone healing.

BACKGROUND: Although bone repair is often a relatively rapid and efficient process, many bone defects do not heal. Because an adequate blood supply is essential for new bone formation, we hypothesized that augmenting new blood vessel formation by increasing the number of circulating vasculogenic progenitor cells (PCs) with AMD3100 and enhancing their trafficking to the site of injury with recombinant human parathyroid hormone (rhPTH) will improve healing. METHODS: Critical-sized 3-mm cranial defects were trephined into the right parietal bone of C57BLKS/J 6 mice (N = 120). The mice were divided into 4 equal groups (n = 30 for each). The first group received daily subcutaneous injections of AMD3100 (5 mg/kg). The second group received daily subcutaneous injections of rhPTH (5 mg/kg). The third group received both AMD3100 and rhPTH. The fourth group received subcutaneous injections of saline. Circulating vasculogenic PC numbers, new blood vessel formation, and bony regeneration were assessed. Progenitor cell adhesion, migration, and tubule formation were assessed in the presence of rhPTH and AMD3100. RESULTS: Flow cytometry demonstrated that combination therapy significantly increased the number of circulating PCs compared with all other groups. In vitro, AMD3100-treated PCs had significantly increased adhesion migration, and tubule formation was assessed in the presence of rhPTH. Combination therapy significantly improved new blood vessel formation in those with cranial defect compared with all other groups. Finally, bony regeneration was significantly increased in the combination therapy group compared with all other groups. CONCLUSIONS: The combination of a PC-mobilizing and traffic-enhancing agent improved bony regeneration of calvarial defects in mice.

Combination therapy accelerates diabetic wound closure.

BACKGROUND: Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis. METHODS AND RESULTS: Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 µg; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%. CONCLUSIONS: Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.

The influence of environmental factors on bone tissue engineering.

Bone repair and regeneration are dynamic processes that involve a complex interplay between the substrate, local and systemic cells, and the milieu. Although each constituent plays an integral role in faithfully recreating the skeleton, investigators have long focused their efforts on scaffold materials and design, cytokine and hormone administration, and cell-based therapies. Only recently have the intangible aspects of the milieu received their due attention. In this review, we highlight the important influence of environmental factors on bone tissue engineering.

Zmpste24-/- mouse model for senescent wound healing research.

BACKGROUND: The graying of our population has motivated the authors to better understand age-related impairments in wound healing. To increase research throughput, the authors hypothesized that the Hutchinson-Gilford progeria syndrome Zmpste24-deficient (Zmpste24(-/-)) mouse could serve as a model of senescent wound healing. METHODS: Using a stented excisional wound closure model, the authors tested this hypothesis on 8-week-old male Zmpste24(-/-) mice (n = 25) and age-matched male C57BL/6J wild-type mice (n = 25). Wounds were measured photogrammetrically and harvested for immunohistochemistry, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction, and circulating vasculogenic progenitor cells were measured by flow cytometry. RESULTS: Zmpste24(-/-) mice had a significant delay in wound closure compared with wild-type mice during the proliferative/vasculogenic phase. Zmpste24(-/-) wounds had decreased proliferation, increased 8-hydroxy-2'-deoxyguanosine levels, increased proapoptotic signaling (i.e., p53, PUMA, BAX), decreased antiapoptotic signaling (i.e., Bcl-2), and increased DNA fragmentation. These changes correlated with decreased local vasculogenic growth factor expression, decreased mobilization of bone marrow-derived vasculogenic progenitor cells, and decreased new blood vessel formation. Age-related impairments in wound closure are multifactorial. CONCLUSIONS: The authors' data suggest that the Hutchinson-Gilford progeria syndrome Zmpste24(-/-) progeroid syndrome shares mechanistic overlap with normal aging and therefore might provide a uniquely informative model with which to study age-associated impairments in wound closure.

Obesity impairs wound closure through a vasculogenic mechanism.

Since obesity impairs wound healing and bone marrow (BM)-derived vasculogenic progenitor cells (PCs) are important for tissue repair, we hypothesize that obesity-impaired wound healing is due, in part, to impaired PC mobilization, trafficking, and function. Peripheral blood was obtained from nondiabetic, obese (BMI > 30, n = 25), and nonobese (BMI < 30, n = 17) subjects. Peripheral blood human (h)PCs were isolated, quantified, and functionally assessed. To corroborate the human experiments, 6-mm stented wounds were created on nondiabetic obese mice (TALLYHO/JngJ, n = 15) and nonobese mice (SWR/J, n = 15). Peripheral blood mouse (m)PCs were quantified and wounds were analyzed. There was no difference in the number of baseline circulating hPCs in nondiabetic, obese (hPC-ob), and nonobese (hPC-nl) subjects, but hPC-ob had impaired adhesion (p < 0.05), migration (p < 0.01), and proliferation (p < 0.001). Nondiabetic obese mice had a significant decrease in the number of circulating PCs (mPC-ob) at 7 (p = 0.008) and 14 days (p = 0.003) after wounding. The impaired circulating mPC-ob response correlated with significantly impaired wound closure at days 14 (p < 0.001) and 21 (p < 0.001) as well as significantly fewer new blood vessels in the wounds (p < 0.001). Our results suggest that obesity impairs the BM-derived vasculogenic PC response to peripheral injury and this, in turn, impairs wound closure.

Bony engineering using time-release porous scaffolds to provide sustained growth factor delivery.

Microporous scaffolds designed to improve bony repair have had limited success; therefore, we sought to evaluate whether time-released porous scaffolds with or without recombinant bone morphogenetic protein 2 (rhBMP-2) could enhance stem cell osteoinduction. Custom-made 15/85 hydroxyapatite/ß-tricalcium phosphate scaffolds were left empty (E) or filled with rhBMP-2 (E+), calcium sulfate (CS), or CS and rhBMP-2 (CS+). All scaffolds were placed in media and weighed daily. Conditioned supernatant was analyzed for rhBMP-2 and then used to feed human adipose-derived mesenchymal stem cells (ASCs). Adipose-derived mesenchymal stem cell ALP activity, OSTERIX expression, and bone nodule formation were determined. E scaffolds retained 97% (SD, 2%) of the initial weight, whereas CS scaffolds had a near-linear 30% (SD, 3%) decrease over 60 days. E+ scaffolds released 155 (SD, 5) ng of rhBMP-2 (77%) by day 2. In contrast, CS+ scaffolds released only 30 (SD, 2) ng (10%) by day 2, and the remaining rhBMP-2 was released over 20 days. Conditioned media from E+ scaffolds stimulated the highest ALP activity and OSTERIX expression in ACSs on day 2. However, after day 6, media from CS+ scaffolds stimulated the highest ALP activity and OSTERIX expression in ASCs. Adipose-derived mesenchymal stem cells exposed to day 8 CS+-conditioned media produced significantly more bone nodules (10.1 [SD, 1.7] nodules per high-power field) than all other scaffolds. Interestingly, day 8 conditioned media from CS scaffolds simulated significantly more bone nodules than either E or E+ scaffold (P < 0.05 for both). Time-released hydroxyapatite/ß-tricalcium phosphate porosity provides sustained growth factor release, enhances ASC osteoinduction, and may result in better in vivo bone formation.

Endogenous stem cell therapy enhances fat graft survival.

BACKGROUND: Lipoaspirate centrifugation creates graded density of adipose tissue. High-density fat contains more vasculogenic cytokines and progenitor cells and has greater graft survival than low-density fat. The authors hypothesize that accelerating the bone marrow-derived progenitor cell response to injected low-density fat will improve its graft survival. METHODS: Male 8-week-old FVB mice (n=60) were grafted with either high-density (n=20) or low-density (n=40) human lipoaspirate. Half of the mice receiving low-density fat (n=20) were treated with a stem cell mobilizer for 14 days. Grafted fat was harvested at 2 and 10 weeks for analysis. RESULTS: Low-density fat, low-density fat plus daily AMD3100, and high-density fat had 26±3.0, 61.2±7.5, and 49.6±3.5 percent graft survival, respectively, at 2 weeks (low-density fat versus low-density fat plus daily AMD3100 and low-density fat versus high-density fat, both p<0.01). Similar results were observed 10 weeks after grafting. Mice receiving low-density fat plus daily AMD3100 had significantly more vasculogenic progenitor cells per cubic centimeter of peripheral blood (p<0.01) and more new blood vessels (p<0.01). Both low-density fat plus daily AMD3100 and high-density fat contained more stromal-derived factor-1α and vascular endothelial growth factor mRNA/protein. CONCLUSION: Endogenous progenitor cell mobilization enhances low-density fat neovascularization, increases vasculogenic cytokine expression, and improves graft survival to a level equal to that of high-density fat grafts.