Publications by authors named "Mimi R Borrelli"

58 Publications

Mentorship amid the Madness: The Value of National Mentorship Programs in Plastic Surgery Amid the COVID-19 Pandemic.

Plast Reconstr Surg 2021 Jul 9. Epub 2021 Jul 9.

Department of Plastic and Reconstructive Surgery Rhode Island Hospital Providence, R.I. Rhode Island Hospital.

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http://dx.doi.org/10.1097/PRS.0000000000008117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312334PMC
July 2021

Striae Distensae: Scars without Wounds.

Plast Reconstr Surg 2021 Jul;148(1):77-87

From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine.

Summary: Striae distensae, or stretch marks, are common linear lesions of atrophic skin characterized histologically by epidermal atrophy, absent rete ridges, and alterations in connective tissue architecture. Hormonal excess, mechanical stress, and genetic predisposition are all associated with striae distensae, but their exact pathogenesis remains unknown. Despite a multitude of options, no single treatment has yet proven effective. In this article, the authors describe an up-to-date overview of striae distensae in terms of their etiology, pathophysiology, and therapeutic options. Further research is required to better elucidate their pathophysiology and to develop targeted effective treatments.
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http://dx.doi.org/10.1097/PRS.0000000000008065DOI Listing
July 2021

Stevens-Johnson syndrome and toxic epidermal necrolysis: a 10-year experience in a burns unit.

J Wound Care 2021 Jun;30(6):492-496

Department of Plastic and Hand Surgery, Burn Unit, Trauma Center Bergmannstrost Halle, Halle, Germany.

Objective: Stevens-Johnson syndrome (SJS) and its more severe counterpart, toxic epidermal necrolysis (TEN), are skin hypersensitivity reactions defined by epidermal blistering and necrosis. The exact pathophysiology of SJS/TEN is yet to be deciphered, but a number of risk factors have been identified including adverse drug reactions. The diagnosis of SJS/TEN is made on a clinical basis, and treatment consists of supportive care and occasionally immunosuppressants, such as cyclosporin, high-dose intravenous immunoglobulins and/or corticosteroids. Mortality rates can reach 20-25% in adults but are reduced with early intervention. To identify optimal treatment regimens, to better understand the patient cohort affected, and to help identify key risk factors for mortality, we report our experience with the treatment and management of SJS/TEN patients.

Methods: A retrospective review of consecutive patients with SJS and/or TEN admitted to a single burns centre in Germany, between 2008 and 2018, was conducted. The primary outcomes of demographics, clinical course, treatment and patient-reported outcomes were recorded and compared with a control group of patients with burns without a diagnosis of SJS/TEN.

Results: A total of 23 patients with SJS/TEN met the inclusion criteria: 17 (74%) with TEN; four (17%) with SJS/TEN overlap; and two (9%) with SJS. Of the patients, 14 (61%) were female and nine (39%) were male. Patient age ranged from 32-78 years (mean: 52 years). A matched cohort of 23 patients with burns served as the control group. All patients received standard of care with a multidisciplinary team. Compared with the control group, SJS/TEN patients had higher mortality rates (n=6, 26% versus n=8, 35%, respectively). The average age of death was 69 years in SJS/TEN patients versus 63 years in control group patients. Age and SCORTEN scores were significant predictors of mortality.

Conclusions: SJS and TEN are rare but extreme reactions of the skin and mucosa, associated with high disease mortality rates. This 10-year single-centre retrospective review contributes to the bank of information for reviews evaluating the management of SJS/TEN patients.
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http://dx.doi.org/10.12968/jowc.2021.30.6.492DOI Listing
June 2021

Risk factors for cooking-related burn injuries in children, WHO Global Burn Registry.

Bull World Health Organ 2021 Jun 1;99(6):439-445. Epub 2021 Apr 1.

Department of Surgery, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21230, United States of America (USA).

Objective: To assess the characteristics of cooking-related burn injuries in children reported to the World Health Organization Global Burn Registry.

Methods: On 1 February 2021, we downloaded data from the Global Burn Registry on demographic and clinical characteristics of patients younger than 19 years. We performed multivariate regressions to identify risk factors predictive of mortality and total body surface area affected by burns.

Findings: Of the 2957 paediatric patients with burn injuries, 974 involved cooking (32.9%). More burns occurred in boys (532 patients; 54.6%) than in girls, and in children 2 years and younger (489 patients; 50.2%). Accidental contact and liquefied petroleum caused most burn injuries (729 patients; 74.8% and 293 patients; 30.1%, respectively). Burn contact by explosions (odds ratio, OR: 2.8; 95% confidence interval, CI: 1.4-5.7) or fires in the cooking area (OR: 3.0; 95% CI: 1.3-6.8), as well as the cooking fuels wood (OR: 2.2; 95 CI%: 1.3-3.4), kerosene (OR: 1.9; 95% CI: 1.0-3.6) or natural gas (OR: 1.5; 95% CI: 1.0-2.2) were associated with larger body surface area affected. Mortality was associated with explosions (OR: 7.5; 95% CI: 2.2-25.9) and fires in the cooking area (OR: 6.9; 95% CI: 1.9-25.7), charcoal (OR: 4.6; 95% CI: 2.0-10.5), kerosene (OR: 3.9; 95% CI: 1.4-10.8), natural gas (OR: 3.0; 95% CI: 1.5-6.1) or wood (OR: 2.8; 95% CI: 1.1-7.1).

Conclusion: Preventive interventions directed against explosions, fires in cooking areas and hazardous cooking fuels should be implemented to reduce morbidity and mortality from cooking-related burn injuries.
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http://dx.doi.org/10.2471/BLT.20.279786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164180PMC
June 2021

Comparing Outcomes of Flap-Based Salvage Reconstructions in the Radiated Breast.

Ann Plast Surg 2021 05;86(5S Suppl 3):S403-S408

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Stanford, CA.

Introduction: Chest wall irradiation significantly decreases the strength and quality of breast tissue supporting prostheses, increasing the risk of skin breakdown and implant or tissue expander extrusion. Autologous tissue, including the latissimus dorsi (LD) or abdominal-based flaps, including the muscle-sparing transverse rectus abdominis myocutaneous or deep inferior epigastric perforator flaps, may be used to salvage reconstructions. However, data comparing outcomes of the two flap options remains limited. We compare postoperative outcomes from both flap types after autologous salvage reconstruction in irradiated breasts.

Methods: Charts were retrospectively reviewed from patients who underwent either chest wall radiation or postmastectomy radiation therapy followed by salvage autologous reconstruction with either a LD and an implant or an abdominal-based flap (muscle-sparing transverse rectus abdominis myocutaneous or deep inferior epigastric perforator flaps). Patients with a history of tissue expander or implant failure requiring autologous salvage as part of 2-staged or delayed-immediate breast reconstruction that were operated on between January 2005 and November 2015 were included. Basic demographics, comorbidities, and recipient site complications (infection, wound dehiscence, seroma, hematoma, fat necrosis, and flap failure) were collected.

Results: A total of 72 patients met the inclusion criteria which included 72 flaps; 35 LD and 37 abdominally based flaps. Demographics and comorbidities did not vary significantly between patient groups. Mean follow-up was 767.6 weeks, and all reconstructions were unilateral. Nineteen (26.4%) patients had at least one complication, most commonly minor infections (9.7%). Overall complication rates were not significantly different between flap groups (P = 0.083). Wound dehiscence was significantly higher in the abdominal group (P = 0.045), and fat necrosis also trended higher in this group (P = 0.085). Major infection trended higher in the latissimus group (P = 0.069).

Conclusions: When comparing outcomes of salvage flap-based reconstruction in radiated breast tissue, overall complication rates were similar when comparing postoperative outcomes between the LD- and abdominal-based flaps. Wound dehiscence was significantly higher when salvage reconstruction used an abdominal flap. Understanding the complications after salvage procedures can help inform decision making and optimize patient care to improve outcomes after breast reconstruction in the radiated breast.
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http://dx.doi.org/10.1097/SAP.0000000000002761DOI Listing
May 2021

Examining the Effects of Postmastectomy Radiation Therapy in Prepectoral Versus Subpectoral Autologous Breast Reconstruction.

Ann Plast Surg 2021 05;86(5S Suppl 3):S390-S394

Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, Palo Alto, CA.

Background: Postmastectomy radiation therapy (PMRT) is known to increase the risk of multiple adverse outcomes after breast reconstruction. In the context of delayed-immediate autologous breast reconstruction, PMRT is typically conducted after placement of subpectoral (SP) tissue expanders. With the re-emergence of prepectoral (PP) reconstruction, there are little data assessing the outcomes of PP reconstruction in breasts receiving PMRT. We compared postoperative outcomes of PMRT patients undergoing delayed-immediate, autologous breast reconstruction with placement of tissue expanders in either the PP or SP plane.

Methods: A retrospective chart review was conducted on all consecutive patients who underwent delayed-immediate autologous breast reconstruction and received PMRT at either the Stanford University or the Johns Hopkins University Hospitals between January 2009 and December 2018. Demographics, comorbidities, perioperative information, and oncologic data were collected for all patients. Complications were collected and analyzed after stage 1 surgery, between 30 days of stage 1 and up to stage 2 surgery, and after stage 2 surgery. Multivariable regressions were used to determine predictors of 1 or more complications.

Results: A total of 71 patients (73 breasts) were included. Prepectoral reconstruction comprised of 52.2% of the cohort, and the remaining 47.8% were SP reconstructions. Demographics and comorbidities were similar between groups, except for premastectomy radiation, which was more prevalent in the PP cohort (P = 0.010). Complications were similar between cohorts after stage 1 surgery (P = 0.420), between stages 1 and 2 (P = 0.100), and after stage 2 (P = 0.570). There were higher rates of skin necrosis in the SP cohort between stages 1 and 2 (PP: 2.6%, SP: 20%, P = 0.004). Multivariable analysis revealed body mass index to be the only predictor of complication (P = 0.041). The mean number of revisionary surgeries was higher in the SP cohort (PP: 0.8 vs SP: 1.9, P = 0.002). The mean follow-up was 385.5 days and similar between groups (P = 0.870).

Conclusions: Rates of overall complication were similar between PP and SP expander placement. However, in SP reconstructions, skin necrosis was significantly higher between stages 1 and 2. The patients in the SP cohort also underwent a greater number of revisionary surgeries, although overall rates of pursuing any revisionary surgery were similar between groups.
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http://dx.doi.org/10.1097/SAP.0000000000002762DOI Listing
May 2021

Preventing activation in fibroblasts yields wound regeneration without scarring.

Science 2021 04;372(6540)

Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.

Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. lineage-positive fibroblasts (EPFs) are known to function in scarring, but lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).
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http://dx.doi.org/10.1126/science.aba2374DOI Listing
April 2021

Gender-Affirming Health Insurance Reform in the United States.

Ann Plast Surg 2021 Aug;87(2):119-122

From the Division of Plastic Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

Introduction: In May 2014, the US Department of Health and Human Services prohibited insurance discrimination of transgender individuals. Despite this, insurance plans often lack explicit guidelines on gender transition-related care and coverage of surgical procedures is extremely varied. We evaluated the evolution of insurance coverage of gender-affirming care following the 2014 legislative change.

Methods: Insurance providers were selected based on company market share. We conducted a Web-based search and telephone interviews to identify the corresponding policies related to gender-affirming health care. We compared policy changes made before and after the 2014 US Department of Health and Human Services decision.

Results: Of the 92 insurers surveyed, 7% did not have a policy, and 315 policy revisions were documented. After the legislation, a significantly higher proportion of policy revisions were related to coverage of services (36% vs 11%, P < 0.0001), removal of existing criteria significantly decreased (23% vs 49%, P = 0.0044), and addition of criteria unrelated to international standards sharply increased (32% vs 2%, P = 0.0002). This resulted in reduced coverage of facial feminization, hair transplantation, laryngochondroplasty, and voice modification surgery. However, nipple reconstruction experienced increased coverage. The percentage of revisions to add preauthorization criteria to meet international standards (49% vs 45%, P = 0.6714) or to change terminology (37% vs 27%, P = 0.1055) were similar before and after the legislation.

Conclusions: After the transformative legislation in 2014, an increasing number of insurance companies established gender transition-related policies. As more patients seek gender-affirming care, insurers deviate from international guidelines and create additional benchmarks that may act as barriers to care.
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http://dx.doi.org/10.1097/SAP.0000000000002674DOI Listing
August 2021

Craniofacial and Long Bone Development in the Context of Distraction Osteogenesis.

Plast Reconstr Surg 2021 01;147(1):54e-65e

From the Department of Surgery, Division of Plastic and Reconstructive Surgery, and the Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine.

Background: Bone retains regenerative potential into adulthood, and surgeons harness this plasticity during distraction osteogenesis. The underlying biology governing bone development, repair, and regeneration is divergent between the craniofacial and appendicular skeleton. Each type of bone formation is characterized by unique molecular signaling and cellular behavior. Recent discoveries have elucidated the cellular and genetic processes underlying skeletal development and regeneration, providing an opportunity to couple biological and clinical knowledge to improve patient care.

Methods: A comprehensive literature review of basic and clinical literature regarding craniofacial and long bone development, regeneration, and distraction osteogenesis was performed.

Results: The current understanding in craniofacial and long bone development and regeneration is discussed, and clinical considerations for the respective distraction osteogenesis procedures are presented.

Conclusions: Distraction osteogenesis is a powerful tool to regenerate bone and thus address a number of craniofacial and appendicular skeletal deficiencies. The molecular mechanisms underlying bone regeneration, however, remain elusive. Recent work has determined that embryologic morphogen gradients constitute important signals during regeneration. In addition, striking discoveries have illuminated the cellular processes underlying mandibular regeneration during distraction osteogenesis, showing that skeletal stem cells reactivate embryologic neural crest transcriptomic processes to carry out bone formation during regeneration. Furthermore, innovative adjuvant therapies to complement distraction osteogenesis use biological processes active in embryogenesis and regeneration. Additional research is needed to further characterize the underlying cellular mechanisms responsible for improved bone formation through adjuvant therapies and the role skeletal stem cells play during regeneration.
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http://dx.doi.org/10.1097/PRS.0000000000007451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773036PMC
January 2021

The quality of online information regarding non-surgical aesthetic procedures.

J Plast Reconstr Aesthet Surg 2021 Aug 10;74(8):1881-1887. Epub 2020 Dec 10.

Surgical Department, King's College Hospital, London, United Kingdom.

Background: The rapid growth of non-surgical aesthetics has led to a scarcity of regulation that raises concerns for serious consequences to public health. Services are advertised primarily through websites which are not necessarily centrally monitored or maintained to a set gold standard. We quantitatively assess the quality of online information regarding non-surgical procedures in order to promote patient safety and informed decision making.

Methods: Google and Bing, search engines that represent 95.27of global searches, were queried with the expanded search terms "facial filler" and "Botox". The top 100 results were sampled and two validated tools were used to assess the quality of healthcare information retrieved; the DISCERN instrument and the JAMA benchmark criteria.

Results: Once duplicates were removed, a total of 77 unique websites were retrieved by the search. The majority of websites were published by private marketing firms. The median score for website quality across all included websites was 'fair' (42) when assessed according to the DISCERN instrument, and 'poor' (1) when assessed against the JAMA criteria. Private websites had the lowest quality of information online and institutional websites had the highest.

Conclusion: Non-surgical aesthetics are becoming increasingly popular with patients and clinicians due to their convenience, scope of treatment, and novel and strategic marketing. Online information available to patients, however, is often of poor quality, dominated by private clinics and commercial entities, and thus presents a significant risk of misinforming patients desiring to undertake these procedures. Significant reform and regulation of information is required in order to make this industry safer for patients.
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http://dx.doi.org/10.1016/j.bjps.2020.12.006DOI Listing
August 2021

Global Burn Registry Perspective on Head and Neck Burns.

Ann Plast Surg 2021 07;87(1):33-38

From the Division of Plastic Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

Introduction: As exposed regions of the body, the head and neck are at increased risk of burn injury. The cosmetic and functional importance of these anatomical regions means that burns can result in substantial morbidity and mortality. Our objective was to characterize predictive factors for surgery and discharge condition in patients with head and neck burns internationally.

Methods: We conducted an epidemiological study of all head and neck burns in 14 countries reported in the World Health Organization Global Burn Registry. Multivariate regression was used to identify variables predictive of surgical treatment and discharge condition.

Results: We identified 1014 patients who sustained head and neck burns; the majority were adults (60%). Both adults and children admitted to hospital with head and neck burn injuries were less likely to be treated surgically in lower-middle-income countries (LMIC) than in higher-income countries (P < 0.001). Increasing age and greater total surface body area (TBSA) were significant predictors of surgical intervention in children with head and neck burn injuries (P < 0.001). Total surface body area, associated injuries, ocular burns, female sex, and LMIC residency were all significant predictors of mortality in adult patients with head and neck burns (P < 0.050). Conversely, TBSA was the only variable that independently increased the risk of death in children with head and neck burns (P < 0.001).

Conclusions: Certain groups are at increased risk of an adverse outcome after admission with a head and neck burn injury. Given the reduced incidence of surgical intervention and the elevated mortality risk in LMICs, global health initiatives should be targeted to these countries.
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http://dx.doi.org/10.1097/SAP.0000000000002585DOI Listing
July 2021

Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis.

Cell Rep 2020 11;33(6):108356

Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305, USA. Electronic address:

Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential.
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http://dx.doi.org/10.1016/j.celrep.2020.108356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7742512PMC
November 2020

Navigating the Insurance Landscape for Coverage of Reduction Mammaplasty.

Plast Reconstr Surg 2020 11;146(5):539e-547e

From the Yorkshire and Humber Foundation School; the Division of Plastic Surgery, Department of Surgery, University of Maryland School of Medicine; and Stanford University School of Medicine.

Background: Reduction mammaplasty provides symptomatic relief to patients with macromastia. Insurance companies act as gatekeepers of health care by determining the medical necessity of surgical procedures, including reduction mammaplasty. The authors sought to evaluate insurance coverage and policy criteria for reduction mammaplasty.

Methods: The authors conducted a cross-sectional analysis of U.S. insurance policies on reduction mammaplasty. Insurance providers were selected based on their enrolment data and market share. The authors conducted telephone interviews and Web-based searches to identify the policies. Medical necessity criteria were abstracted from the publicly available policies that offered coverage.

Results: The authors reviewed 63 insurers. One in 10 insurers had no established policy for reduction mammaplasty. Of the 48 publicly available policies, shoulder pain and backache were the most common symptoms required for preapproval (98 percent and 98 percent). A minimum resection volume was requested by 88 percent of policies. One-third of policies (31 percent) offered a choice between removal of a minimum weight per breast or a volume based on body surface area. Over half of companies (54 percent) used body surface area calculations to predict minimum resection volume. Medical necessity that extended beyond national recommendations included trial of weight loss (23 percent) and nipple position (10 percent).

Conclusions: Insurance policy criteria for reduction mammaplasty are discordant with current national recommendations and current clinical evidence. Many policies use outdated criteria that do not correlate with symptom relief and consequently limit access to reduction mammaplasty. Here, the authors propose a comprehensive guideline to maximize coverage of reduction mammaplasty.
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http://dx.doi.org/10.1097/PRS.0000000000007241DOI Listing
November 2020

Characterization of Diabetic and Non-Diabetic Foot Ulcers Using Single-Cell RNA-Sequencing.

Micromachines (Basel) 2020 Aug 28;11(9). Epub 2020 Aug 28.

Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.

Recent advances in high-throughput single-cell sequencing technologies have led to their increasingly widespread adoption for clinical applications. However, challenges associated with tissue viability, cell yield, and delayed time-to-capture have created unique obstacles for data processing. Chronic wounds, in particular, represent some of the most difficult target specimens, due to the significant amount of fibrinous debris, extracellular matrix components, and non-viable cells inherent in tissue routinely obtained from debridement. Here, we examined the feasibility of single cell RNA sequencing (scRNA-seq) analysis to evaluate human chronic wound samples acquired in the clinic, subjected to prolonged cold ischemia time, and processed without FACS sorting. Wound tissue from human diabetic and non-diabetic plantar foot ulcers were evaluated using an optimized 10X Genomics scRNA-seq platform and analyzed using a modified data pipeline designed for low-yield specimens. Cell subtypes were identified informatically and their distributions and transcriptional programs were compared between diabetic and non-diabetic tissue. 139,000 diabetic and non-diabetic wound cells were delivered for 10X capture after either 90 or 180 min of cold ischemia time. cDNA library concentrations were 858.7 and 364.7 pg/µL, respectively, prior to sequencing. Among all barcoded fragments, we found that 83.5% successfully aligned to the human transcriptome and 68% met the minimum cell viability threshold. The average mitochondrial mRNA fraction was 8.5% for diabetic cells and 6.6% for non-diabetic cells, correlating with differences in cold ischemia time. A total of 384 individual cells were of sufficient quality for subsequent analyses; from this cell pool, we identified transcriptionally-distinct cell clusters whose gene expression profiles corresponded to fibroblasts, keratinocytes, neutrophils, monocytes, and endothelial cells. Fibroblast subpopulations with differing fibrotic potentials were identified, and their distributions were found to be altered in diabetic vs. non-diabetic cells. scRNA-seq of clinical wound samples can be achieved using minor modifications to standard processing protocols and data analysis methods. This simple approach can capture widespread transcriptional differences between diabetic and non-diabetic tissue obtained from matched wound locations.
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http://dx.doi.org/10.3390/mi11090815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570277PMC
August 2020

Delivery of Human Stromal Vascular Fraction Cells on Nanofibrillar Scaffolds for Treatment of Peripheral Arterial Disease.

Front Bioeng Biotechnol 2020 17;8:689. Epub 2020 Jul 17.

Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States.

Cell therapy for treatment of peripheral arterial disease (PAD) is a promising approach but is limited by poor cell survival when cells are delivered using saline. The objective of this study was to examine the feasibility of aligned nanofibrillar scaffolds as a vehicle for the delivery of human stromal vascular fraction (SVF), and then to assess the efficacy of the cell-seeded scaffolds in a murine model of PAD. Flow cytometric analysis was performed to characterize the phenotype of SVF cells from freshly isolated lipoaspirate, as well as after attachment onto aligned nanofibrillar scaffolds. Flow cytometry results demonstrated that the SVF consisted of 33.1 ± 9.6% CD45 cells, a small fraction of CD45/CD31 (4.5 ± 3.1%) and 45.4 ± 20.0% of CD45/CD31/CD34 cells. Although the subpopulations of SVF did not change significantly after attachment to the aligned nanofibrillar scaffolds, protein secretion of vascular endothelial growth factor (VEGF) significantly increased by six-fold, compared to SVF cultured in suspension. Importantly, when SVF-seeded scaffolds were transplanted into immunodeficient mice with induced hindlimb ischemia, the cell-seeded scaffolds induced a significant higher mean perfusion ratio after 14 days, compared to cells delivered using saline. Together, these results show that aligned nanofibrillar scaffolds promoted cellular attachment, enhanced the secretion of VEGF from attached SVF cells, and their implantation with attached SVF cells stimulated blood perfusion recovery. These findings have important therapeutic implications for the treatment of PAD using SVF.
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http://dx.doi.org/10.3389/fbioe.2020.00689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380169PMC
July 2020

Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review.

Plast Reconstr Surg Glob Open 2020 Jun 23;8(6):e2927. Epub 2020 Jun 23.

Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif.

Fibroblasts' integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of "fibroblast heterogeneity." Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery-for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), "pathological" scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.
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http://dx.doi.org/10.1097/GOX.0000000000002927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339369PMC
June 2020

Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis.

Sci Rep 2020 07 23;10(1):12346. Epub 2020 Jul 23.

Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA.

Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.
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http://dx.doi.org/10.1038/s41598-020-69293-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378074PMC
July 2020

The antifibrotic adipose-derived stromal cell: Grafted fat enriched with CD74+ adipose-derived stromal cells reduces chronic radiation-induced skin fibrosis.

Stem Cells Transl Med 2020 11 20;9(11):1401-1413. Epub 2020 Jun 20.

Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California, USA.

Fat grafting can reduce radiation-induced fibrosis. Improved outcomes are found when fat grafts are enriched with adipose-derived stromal cells (ASCs), implicating ASCs as key drivers of soft tissue regeneration. We have identified a subpopulation of ASCs positive for CD74 with enhanced antifibrotic effects. Compared to CD74- and unsorted (US) ASCs, CD74+ ASCs have increased expression of hepatocyte growth factor, fibroblast growth factor 2, and transforming growth factor β3 (TGF-β3) and decreased levels of TGF-β1. Dermal fibroblasts incubated with conditioned media from CD74+ ASCs produced less collagen upon stimulation, compared to fibroblasts incubated with media from CD74- or US ASCs. Upon transplantation, fat grafts enriched with CD74+ ASCs reduced the stiffness, dermal thickness, and collagen content of overlying skin, and decreased the relative proportions of more fibrotic dermal fibroblasts. Improvements in several extracellular matrix components were also appreciated on immunofluorescent staining. Together these findings indicate CD74+ ASCs have antifibrotic qualities and may play an important role in future strategies to address fibrotic remodeling following radiation-induced fibrosis.
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http://dx.doi.org/10.1002/sctm.19-0317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581454PMC
November 2020

CD34+CD146+ adipose-derived stromal cells enhance engraftment of transplanted fat.

Stem Cells Transl Med 2020 11 15;9(11):1389-1400. Epub 2020 Jun 15.

Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California, USA.

Fat grafting is a surgical technique able to reconstruct and regenerate soft tissue. The adipose-derived stromal cells (ASCs) within the stromal vascular fraction are believed to drive these beneficial effects. ASCs are increasingly recognized to be a heterogeneous group, comprised of multiple stem and progenitor subpopulations with distinct functions. We hypothesized the existence of an ASC subpopulation with enhanced angiogenic potential. Human ASCs that were CD34+CD146+, CD34+CD146-, or CD34+ unfractionated (UF) were isolated by flow cytometry for comparison of expression of proangiogenic factors and endothelial tube-forming potential. Next, lipoaspirate was enriched with either CD34+CD146+, CD34+CD146-, CD34+ UF ASCs, or was not enriched, and grafted beneath the scalp skin of immunodeficient CD-1 Nude mice (10 000 cells/200 μL/graft). Fat retention was monitored radiographically more than 8 weeks and fat grafts were harvested for histological assessment of quality and vascularization. The CD34+CD146+ subpopulation comprised ~30% of ASCs, and exhibited increased expression of vascular endothelial growth factor and angiopoietin-1 compared to CD34+CD146- and CD34+ UF ASCs, and increased expression of fibroblast growth factor-2 compared to CD34+CD146- ASCs. The CD34+CD146+ subpopulation exhibited enhanced induction of tube-formation compared to CD34+CD146- ASCs. Upon transplantation, fat enriched CD34+CD146+ ASCs underwent less resorption and had improved histologic quality and vascularization. We have identified a subpopulation of CD34+ ASCs with enhanced angiogenic effects in vitro and in vivo, likely mediated by increased expression of potent proangiogenic factors. These findings suggest that enriching lipoaspirate with CD34+CD146+ ASCs may enhance fat graft vascularization and retention in the clinical setting.
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http://dx.doi.org/10.1002/sctm.19-0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581443PMC
November 2020

Understanding the impact of fibroblast heterogeneity on skin fibrosis.

Dis Model Mech 2020 06 15;13(6). Epub 2020 Jun 15.

Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford, CA 94305, USA

Tissue fibrosis is the deposition of excessive extracellular matrix and can occur as part of the body's natural wound healing process upon injury, or as a consequence of diseases such as systemic sclerosis. Skin fibrosis contributes to significant morbidity due to the prevalence of injuries resulting from trauma and burn. Fibroblasts, the principal cells of the dermis, synthesize extracellular matrix to maintain the skin during homeostasis and also play a pivotal role in all stages of wound healing. Although it was previously believed that fibroblasts are homogeneous and mostly quiescent cells, it has become increasingly recognized that numerous fibroblast subtypes with unique functions and morphologies exist. This Review provides an overview of fibroblast heterogeneity in the mammalian dermis. We explain how fibroblast identity relates to their developmental origin, anatomical site and precise location within the skin tissue architecture in both human and mouse dermis. We discuss current evidence for the varied functionality of fibroblasts within the dermis and the relationships between fibroblast subtypes, and explain the current understanding of how fibroblast subpopulations may be controlled through transcriptional regulatory networks and paracrine communications. We consider how fibroblast heterogeneity can influence wound healing and fibrosis, and how insight into fibroblast heterogeneity could lead to novel therapeutic developments and targets for skin fibrosis. Finally, we contemplate how future studies should be shaped to implement knowledge of fibroblast heterogeneity into clinical practice in order to lessen the burden of skin fibrosis.
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http://dx.doi.org/10.1242/dmm.044164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328159PMC
June 2020

Comparing Prepectoral Versus Subpectoral Tissue Expander Placement Outcomes in Delayed-Immediate Autologous Breast Reconstruction.

Ann Plast Surg 2020 05;84(5S Suppl 4):S329-S335

From the Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, Palo Alto, CA.

Background: Delayed-immediate breast reconstruction has traditionally involved placement of tissue expanders (TE) in the subpectoral (SP) position. Development of acellular dermal matrices has renewed interest in the prepectoral (PP) pocket, which avoids extensive muscle manipulation. We compare complication rates between PP and SP TE placement in autologous delayed-immediate breast reconstruction.

Methods: A retrospective chart review of patients undergoing autologous, delayed-immediate breast reconstruction at our institution (June 2009 to December 2018) was performed. Demographics, comorbidities, perioperative information, and complication incidence ≤12 months' follow-up were collected from first- and second-stage surgeries. Complications were modeled using univariable and multivariable binary logistic regressions.

Results: A total of 89 patients met the inclusion criteria, and data from 125 breast reconstructions were evaluated. Complication rates following TE placement trended lower in the PP cohort (28.8% vs 37%, P = 0.34). Overall complication rates following autologous reconstruction were significantly lower for PP reconstructions (7.7% vs 23.3%, P = 0.02). Multivariable regression showed TE position (P = 0.01) was a significant predictor of ≥1 complication following autologous reconstruction. Time delay between first- and second-stage surgeries was greater for SP reconstructions (199.7 vs 324.8 days, P < 0.001). Postoperative drains were removed earlier in the PP cohort (8.6 vs 12.0 days, P < 0.001). Mean follow-up time was 331.3 days.

Conclusions: Prepectoral reconstruction in the delayed-immediate autologous reconstruction patient leads to significantly lower complication rates, shorter duration between first- and second-stage surgeries, and shorter times before removal of breast drains compared with SP reconstructions.
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http://dx.doi.org/10.1097/SAP.0000000000002402DOI Listing
May 2020

Compounding Benefits of Sentinel Lymph Node Biopsy for Perineal Melanoma: A Population-Based Retrospective Cohort Analysis.

Ann Plast Surg 2020 05;84(5S Suppl 4):S257-S263

From the Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, Stanford University, Palo Alto, CA.

Introduction: Sentinel lymph node biopsy (SLNB) in the treatment of melanoma is known to provide valuable prognostic information. However, there is no literature describing an overall or disease-specific survival (DDS) benefit of SLNB. In the perineum, melanoma is often more advanced at presentation with current treatment guidelines translated from nonanatomic specific melanoma. As a result, there is little understanding surrounding the role of SLNB in melanoma of the perineum. Our objective is to better understand the therapeutic benefits of SLNB in perineal melanoma.

Methods: The Surveillance, Epidemiology, and End Results program is a large population-based cancer registry including survival data from millions of patients in the United States. The registry was used to generate patient data for analysis from 2004 to 2016. Inclusion criteria included melanoma of the perineum; Breslow depth of 0.80 mm or greater and less than 0.80 mm with ulceration; SLNB or no intervention; clinically negative nodal disease; and available overall survival data.

Results: For 879 patients from 2004 to 2016 with perineal melanoma, significant predictors of reduced survival include older than 75 years, Clark level IV-V, Breslow depth of greater than 4.00 mm, positive ulceration status, regional and distant nodal micrometastases, and clinically positive nodes on presentation. Aggregates for overall survival (OS) and disease-specific survival (DSS) were improved with implementation of SLNB. The 5-year survival rates with SLNB versus no SLNB were 54.0% and 43.0% for OS (P = 0.001) and 57.8% and 53.1% for DSS (P = 0.044). Stratification by Breslow depth yielded significant OS and DSS advantage for greater than 1.00 to 2.00 mm (21.3% benefit, P =0.021, and 16.8% benefit, P = 0.044) and greater than 4.00 mm (30.3% benefit, P = 0.005, and 21.0% benefit, P = 0.007) Breslow depths.

Conclusions And Relevance: Sentinel lymph node biopsy may provide therapeutic benefits in addition to prognostic information for melanoma of the perineum through an increase in 5-year OS.
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http://dx.doi.org/10.1097/SAP.0000000000002388DOI Listing
May 2020

Molecular Mechanisms of Hair Growth and Regeneration: Current Understanding and Novel Paradigms.

Dermatology 2020 12;236(4):271-280. Epub 2020 Mar 12.

Department of Plastic Surgery and Hand Surgery, Technical University Munich, Munich, Germany,

Hair is a defining feature of mammals and has critical functions, including protection, production of sebum, apocrine sweat and pheromones, social and sexual interactions, thermoregulation, and provision of stem cells for skin homeostasis, regeneration, and repair. The hair follicle (HF) is considered a "mini-organ," consisting of intricate and well-organized structures which originate from HF stem and progenitor cells. Dermal papilla cells are the main components of the mesenchymal compartments in the hair bulb and are instrumental in generating signals to regulate the behavior of neighboring epithelial cells during the hair cycle. Mesenchymal-epithelial interactions within the dermal papilla niche drive HF embryonic development as well as the postnatal hair growth and regeneration cycle. This review summarizes the current understanding of HF development, repair, and regeneration, with special focus on cell signaling pathways governing these processes. In particular, we discuss emerging paradigms of molecular signaling governing the dermal papilla-epithelial cellular interactions during hair growth and maintenance and the recent progress made towards tissue engineering of human hair follicles.
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http://dx.doi.org/10.1159/000506155DOI Listing
April 2021

Burns: modified metabolism and the nuances of nutrition therapy.

J Wound Care 2020 Mar;29(3):184-191

7 Department of Plastic Surgery and Burn Centre, BG University Hospital Bergmannsheil GmbH, Ruhr University Bochum, Bochum, Germany.

Objective: To review the effects of burn injury on nutritional requirements and how this can best be supported in a healthcare setting.

Method: A literature search for articles discussing nutrition and/or metabolism following burn injury was carried out. PubMed, Embase and Web of Science databases were searched using the key search terms 'nutrition' OR 'metabolism' AND 'burn injury' OR 'burns'. There was no limitation on the year of publication.

Results: A total of nine articles met the inclusion criteria, the contents of which are discussed in this manuscript.

Conclusion: Thermal injury elicits the greatest metabolic response, among all traumatic events, in critically ill patients. In order to ensure burn patients can meet the demands of their increased metabolic rate and energy expenditure, adequate nutritional support is essential. Burn injury results in a unique pathophysiology, involving alterations in endocrine, inflammatory, metabolic and immune pathways and nutritional support needed during the inpatient stay varies depending on burn severity and idiosyncratic patient physiologic parameters.
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http://dx.doi.org/10.12968/jowc.2020.29.3.184DOI Listing
March 2020

Composite grafts for fingertip amputations: A systematic review protocol.

Int J Surg Protoc 2019 23;16:1-4. Epub 2019 May 23.

Plastic Surgery Department, St Thomas' Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, United Kingdom.

Background: There is much debate in the hand surgery literature as to the management of fingertip amputations. Much research continues to be published in this area. Methods of reattachment include microsurgical and non-microsurgical (composite graft) replantation. The role of composite grafts lacks clarity in terms of outcomes, success rates and complications. Hence there is a need for an evidence synthesis, which can guide patient selection, the consent process and determine graft survival rates and functional outcomes to optimise patient outcomes.

Methods: Search of the databases OVID MEDLINE, PubMed, EMBASE, SCOPUS, The Cochrane Library and clinical trial registries from inception using terms "fingertip" "digital tip" "digit" "finger" "thumb" "amputation" "replantation" "reattachment" "reimplantation" and "composite graft" as key terms with "AND" selected as a Boolean operator, limited to humans will be conducted by two independent researchers. The patient population will include adults and children. Studies will be included if they report: (1) primary data; (2) outcomes of 'composite grafts' or 'nonmicrosurgical replantations'; (3) graft survival, (4) 5 or more cases. Articles will be excluded if surgical techniques involve: (1) composite graft pocketing, or (2) microsurgical replantation or (3) additional flaps (pulp or local). Full exclusion and inclusion criteria are described within this protocol. Data extraction will include; demographic details, patient comorbidities, amputation nature and level, functional, and aesthetic outcomes, complications and need for secondary procedures. All data extracted will be cross-checked, and discrepancies resolved through consensus.

Dissemination: This review will be published in a peer-reviewed journal and will be presented at national and international conferences to inform the practice of other clinicians.
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http://dx.doi.org/10.1016/j.isjp.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921220PMC
May 2019

A systematic review and meta-analysis of antibiotic prophylaxis in skin graft surgery: A protocol.

Int J Surg Protoc 2019 28;14:14-18. Epub 2019 Feb 28.

St Thomas' Hospital, Guy's and St. Thomas' NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK.

Introduction: There is little evidence-based guidance on the use of prophylactic antibiotics in skin surgery; whilst antibiotics may protect against surgical site infections (SSI), they have associated side effects, increase the risk of adverse events, and can propagate antibiotic resistance. We present a protocol for a systematic review to establish whether the benefit of prophylactic antibiotics overrides the risk, for patients undergoing autograft surgery.

Methods: The systematic review will be registered a priori on researchregistry.com and will be conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). A search strategy will be devised to investigate 'skin graft surgery and use of antibiotics'. The following electronic databases will be searched, 1979-2018: PubMed, MEDLINE®, EMBASE, SCOPUS, CINAHL, PsychINFO, SciELO, The Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effect (DARE), the Cochrane Methodology Register, Health Technology Assessment Database, the NHS Economic Evaluation Databases and Cochrane Groups, ClinicalTrials.gov, Current Controlled Trials Database, the World Health Organisation (WHO) International Clinical Trials Registry Platform, UpToDate.com, NHS Evidence and the York Centre for Reviews and Dissemination. Grey literature will be searched. All comparative study designs reporting on the use of antibiotics in skin graft surgery will be considered for inclusion, namely randomized controlled trials (RCTs). Two trained independent teams will screen all titles and abstracts, followed by relevant full texts, for eligibility. Data will be extracted under standardized extraction fields into a preformatted database. Note will be made of the indication for skin graft surgery (traumatic, congenital, malignant, benign), the graft site (head & neck, trunk, upper extremities, lower extremities), type of skin graft (split thickness, full-thickness). The primary outcome will be occurrence of SSI at the donor and/or recipient sites. Secondary outcomes, if reported, will include: length of hospital stay, revision surgery required, cost of medical care, time to wound healing and cosmetic outcome.

Ethics And Dissemination: The systematic review will be published in a peer-reviewed journal and presented at national and international meetings within fields of plastic, reconstructive, and aesthetic surgery. The work will be disseminated electronically and in print. Brief reports of the review and findings will be disseminated to interested parties through email and direct communication. The review aims to guide healthcare practice and policy.
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http://dx.doi.org/10.1016/j.isjp.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913549PMC
February 2019

The versatile free medial sural artery perforator flap: An institutional experience for reconstruction of the head and neck, upper and lower extremities.

Microsurgery 2020 May 10;40(4):427-433. Epub 2019 Dec 10.

Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Background: The medial sural artery perforator (MSAP) flap is an increasingly versatile and reliable flap for soft tissue reconstruction. This study investigates complication rates and long-term outcomes of the MSAP flap.

Methods: A retrospective review was performed on consecutive patients undergoing MSAP flap reconstruction at Chang Gung Memorial Hospital from 2006 through 2017. Patient demographics were assessed. Flap failure and wound complications were the outcome measures.

Results: In the cohort of 246 patients that underwent a total of 248 MSAP flap reconstructions were identified. The average age was 47.5 years (range 15-76). Of the 248 flaps, 170 were used for reconstruction of the head and neck, 48 for upper extremity reconstruction, and 30 for lower extremity reconstruction. The average MSAP flap size was 5.2 × 11.8 cm. 31 (12.5%) of the flaps developed arterial occlusion, venous insufficiency, or a hematoma postoperatively requiring re-exploration. Nineteen were successfully salvaged, yielding an overall failure rate of 4.8%. Minor complications included the need for flap debridement in 18 cases (7.3%) and need for donor site debridement in eight cases (3.2%).

Conclusions: The MSAP flap can be used in a versatile fashion to reconstruct defects of the head and neck, upper extremity, and lower extremity with minimal complication rates.
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http://dx.doi.org/10.1002/micr.30543DOI Listing
May 2020

Fat grafting rescues radiation-induced joint contracture.

Stem Cells 2020 03 3;38(3):382-389. Epub 2019 Dec 3.

Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, Stanford, California.

The aim of this study was to explore the therapeutic effects of fat grafting on radiation-induced hind limb contracture. Radiation therapy (RT) is used to palliate and/or cure a range of malignancies but causes inevitable and progressive fibrosis of surrounding soft tissue. Pathological fibrosis may lead to painful contractures which limit movement and negatively impact quality of life. Fat grafting is able to reduce and/or reverse radiation-induced soft tissue fibrosis. We explored whether fat grafting could improve extensibility in irradiated and contracted hind limbs of mice. Right hind limbs of female 60-day-old CD-1 nude mice were irradiated. Chronic skin fibrosis and limb contracture developed. After 4 weeks, irradiated hind limbs were then injected with (a) fat enriched with stromal vascular cells (SVCs), (b) fat only, (c) saline, or (d) nothing (n = 10/group). Limb extension was measured at baseline and every 2 weeks for 12 weeks. Hind limb skin then underwent histological analysis and biomechanical strength testing. Irradiation significantly reduced limb extension but was progressively rescued by fat grafting. Fat grafting also reduced skin stiffness and reversed the radiation-induced histological changes in the skin. The greatest benefits were found in mice injected with fat enriched with SVCs. Hind limb radiation induces contracture in our mouse model which can be improved with fat grafting. Enriching fat with SVCs enhances these beneficial effects. These results underscore an attractive approach to address challenging soft tissue fibrosis in patients following RT.
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http://dx.doi.org/10.1002/stem.3115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033730PMC
March 2020

Retrospective cohort-based comparison of intraoperative liposomal bupivacaine versus bupivacaine for donor site iliac crest analgesia during alveolar bone grafting.

J Plast Reconstr Aesthet Surg 2019 Dec 2;72(12):2056-2063. Epub 2019 Oct 2.

Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States; Division of Plastic and Reconstructive Surgery, Stanford University Medical Center, 257 Campus Drive West, Stanford, CA 94305, United States. Electronic address:

Introduction: Bone grafting of alveolar clefts is routinely performed with cancellous bone harvested from the iliac crest. Graft site morbidity is frequently seen, with early postoperative pain being one of the most common complaints. Liposomal bupivacaine (LB) has been demonstrated to provide improvement in postoperative pain for patients undergoing bunionectomy or hemorrhoidectomy, which may translate to patients requiring iliac crest bone graft harvest.

Methods: Thirty-eight patients undergoing iliac crest bone harvest were included in the study. Twenty-one patients underwent open iliac crest bone graft harvest with administration of 0.25% bupivacaine at the hip donor site, while 17 patients received local infiltration of 1.3% liposomal bupivacaine. Patient-reported pain scores, total narcotic use, length of stay, and postoperative steps were monitored.

Results: There were no significant differences in age, weight, distribution of clefts, or choice of donor hip between the two groups. There were no significant differences in length of hospitalization stay. However, differences were noted in average postoperative pain scores at five of six time points in the first 24 h, total oral morphine equivalents administered (4.7 ± 5.3 vs. 14.3 ± 12.0), and steps at postoperative days one to three (p < 0.001, for all three days) for patients receiving 1.3% LB versus 0.25% bupivacaine, respectively.

Conclusion: Reduced pain scores and increased postoperative activity highlight the potential of LB to improve postoperative pain management in children undergoing iliac crest bone harvest for alveolar bone grafting.
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http://dx.doi.org/10.1016/j.bjps.2019.09.026DOI Listing
December 2019

Macrophage Transplantation Fails to Improve Repair of Critical-Sized Calvarial Defects.

J Craniofac Surg 2019 Nov-Dec;30(8):2640-2645

Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery.

Introduction: Over 500,000 bone grafting procedures are performed every year in the United States for neoplastic and traumatic lesions of the craniofacial skeleton, costing $585 million in medical care. Current bone grafting procedures are limited, and full-thickness critical-sized defects (CSDs) of the adult human skull thus pose a substantial reconstructive challenge for the craniofacial surgeon. Cell-based strategies have been shown to safely and efficaciously accelerate the rate of bone formation in CSDs in animals. The authors recently demonstrated that supraphysiological transplantation of macrophages seeded in pullalan-collagen composite hydrogels significantly accelerated wound healing in wild type and diabetic mice, an effect mediated in part by enhancing angiogenesis. In this study, the authors investigated the bone healing effects of macrophage transplantation into CSDs of mice.

Methods: CD1 athymic nude mice (60 days of age) were anesthetized, and unilateral full-thickness critical-sized (4 mm in diameter) cranial defects were created in the right parietal bone, avoiding cranial sutures. Macrophages were isolated from FVB-L2G mice and seeded onto hydroxyapatite-poly (lactic-co-glycolic acid) (HA-PLGA) scaffolds (1.0 × 10 cells per CSD). Scaffolds were incubated for 24 hours before they were placed into the CSDs. Macrophage survival was assessed using three-dimensional in vivo imaging system (3D IVIS)/micro-CT. Micro-CT at 0, 2, 4, 6, and 8 weeks was performed to evaluate gross bone formation, which was quantified using Adobe Photoshop. Microscopic evidence of bone regeneration was assessed at 8 weeks by histology. Bone formation and macrophage survival were compared at each time point using independent samples t tests.

Results: Transplantation of macrophages at supraphysiological concentration had no effect on the formation of bones in CSDs as assessed by either micro-CT data at any time point analyzed (all P > 0.05). These results were corroborated by histology. 3D IVIS/micro-CT demonstrated survival of macrophages through 8 weeks.

Conclusion: Supraphysiologic delivery of macrophages to CSDs of mice had no effect on bone formation despite survival of transplanted macrophages through to 8 weeks posttransplantation. Further research into the physiological effects of macrophages on bone regeneration is needed to assess whether recapitulation of these conditions in macrophage-based therapy can promote the healing of large cranial defects.
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http://dx.doi.org/10.1097/SCS.0000000000005797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089774PMC
January 2020
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