Paul S Cederna

University of Michigan, Ann Arbor, Michigan, United States

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Publications (160)257.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Recent research into adipose-derived stem cells (ASCs) suggests that anatomical location has a major impact on the metabolic profile and differentiation capacity of ASCs. By having a better understanding of how various ASCs respond to cellular stressors such as hypoxia, which are induced during routine surgical procedures, we can facilitate future development of cell-based therapies to improve wound healing. Patients and Methods Human ASCs were isolated from the superficial and deep adipose layers of four patients undergoing elective abdominoplasty. ASCs were cultured in hypoxic (1% O2, 5% CO2, and 94% N2) conditions. After 12 and 48 hours, ASCs were assessed for markers of angiogenesis by mRNA levels of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and hypoxia inducible factor 1 α (HIF-1α). Western blot analysis was performed to assess levels of VEGF-A, p-NF-κB, and NF-κB. In addition, in vitro analysis of angiogenesis was performed using Matrigel assay (BD Biosciences, Franklin Lakes, NJ). Results We observed significant increases in deep ASC's VEGF-A, VEGF-B, and HIF-1α mRNA expression compared with the superficial layer after 24-hour hypoxia (p < 0.05). Similar results were found when examining protein expression levels, with the deep ASCs expressing significantly larger amounts of VEGF-A and p-NF-κB (p < 0.05) compared with the superficial layer. Conclusion Our results suggest that significant variations exist in the angiogenic profile of superficial and deep ASCs. We demonstrate that superficial ASCs are less prone to transcribe potent chemokines for angiogenesis, such as VEGF-A, VEGF-B, and HIF-1α and are less likely to translate VEGF-A and NF-κB. This may help with the selection of specific stem cell donor sites in future models for stem cell therapy. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
    Journal of Reconstructive Microsurgery 12/2014; · 1.00 Impact Factor
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    ABSTRACT: After reading this article, the participant should be able to: 1. Describe various wound closure techniques available to the modern plastic surgeon, including the indications and contraindications of each. 2. Explain the fundamental concepts of wound healing as it relates to reconstruction. 3. Understand the role of commonly used reconstructive adjuncts such as negative-pressure wound therapy, dermal substitutes, and tissue expansion. 4. Assess the important patient factors that may influence the strategy for surgical wound closure. Successful wound closure requires a comprehensive approach that includes consideration of suitable surgical techniques and critical patient factors. A clear understanding of key concepts such as wound healing, flap design, and patient risk assessment is imperative to a favorable outcome. In this Maintenance of Certification/Continuing Medical Education article, the reader is provided a summary of the available surgical options for wound closure and a discussion of the algorithm used to choose the most appropriate reconstructive strategy.
    Plastic and reconstructive surgery. 12/2014; 134(6):1391-404.
  • Society for Neuroscience; 11/2014
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    ABSTRACT: BACKGROUND: Over the last decade, use of acellular dermal matrix in both breast surgery and abdominal wall reconstruction has gained popularity. Because the body's ability to integrate ADM, they have been touted as resistant to infection. Although this has been the case in hernia repair, 3 recent meta-analyses have demonstrated an increased risk of infection when used for breast reconstruction. This may be due to the fact that some ADM products are actually not sterile, but instead are "aseptically processed." METHODS: In order to test the sterility of ADM products, five separate 2x4cm samples of 13 different brands of ADM (Table 1) were sterilely cut into 1x1cm pieces and placed in liquid culture media for aerobic/anaerobic bacteria, acid-fast bacilli (AFB), and fungi. Standard culture media was incubated for 2 weeks and AFB for 6 weeks. The Biomerieux Vitek 2 system was used to identify organisms from positive cultures. Separate samples of the ADMs were fixed and processed for paraffin embedding and used for fluorescent in-situ hybridization (FISH) using a universal bacterial DNA probe EUB338 to detect any presence of bacterial DNA on the ADMs. FISH slides were evaluated with confocal microscopy. The Mann-Whitney U test was utilized with p<0.05 considered significant. RESULTS: The following ADMs had positive cultures: AlloDerm (bacillus sp.), AlloDerm RTU (staph warneri), DermaMatrix (staph epidermidis), XCM biologic (bacillus sp., staph warneri), Flex HD (staph warneri), and SurgiMend (staph warneri, staph epidermidis). Of the positive cultures, 3 were from terminally sterilized ADMs, and 3 were from aseptically processed ADMs. Results of FISH demonstrated traces of bacterial DNA on all matrices except for Integra (Table 1, Figure 1). Number of bacteria per high-power field (HPF) on FISH ranged from 0 (Integra) to 13 (AlloDerm) with an average of 2.3. There were more bacteria per HPF in the aseptically processed group compared to the sterile group, although this did not reach significance (3.6 vs. 1.9, p=0.09). CONCLUSION: Standard culture techniques of both sterile and aseptically processed ADMs yielded an equal amount of positive cultures, all of which were standard skin flora and could have been contaminants. FISH analysis demonstrated evidence of prior bacterial contamination on all ADMs with the exception of Integra. Whether these findings are correlated with clinical infections remains to be studied.
    Plastic and reconstructive surgery. 10/2014; 134(4S-1 Suppl):80-81.
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    ABSTRACT: Background:Autologous fat grafting has become a widely used adjunct for refinement of both implant-based and autologous tissue breast reconstruction. However, there are only a few studies evaluating the results of autologous fat grafting in this patient population. The purpose of this study was to assess complication rates and other outcomes of autologous fat grafting following post-mastectomy breast reconstruction. Methods:We retrospectively reviewed the medical records of consecutive post-mastectomy patients who underwent autologous fat grafting after breast reconstruction at a university center over a 5 year period with at least 6 months of follow-up. We reviewed patient demographics; mastectomy and reconstructive operative details; autologous fat grafting information including local and distant/systemic complications; imaging and biopsy rates; and locoregional cancer recurrence rates. Descriptive statistics were generated for these outcomes. Results:Between January 2008 and July 2013 108 women underwent autologous fat grafting for contouring following breast reconstruction. Their ages ranged from 22 to 71 years (mean 48.3 years). Fourty-eight (44.4%) patients underwent unilateral mastectomy, whereas 60 (55.6%) had bilateral mastectomies. For unilateral mastectomy patients, 24 (50%) underwent implant-based reconstruction and 24 (50%) received autologous tissue reconstruction. Among patients with bilateral mastectomies, 15 (25%) underwent implant-based reconstruction, 32 (53.3%) received autologous tissue reconstruction, and 13 (21.7%) underwent combinations of these approaches. Fat grafts were harvested and processed using the Coleman technique1. The volume of fat grafted varied from 15cc to 180cc (mean 54.7cc). Follow up ranged from 6.3 to 57.4 months (mean 16.8 months). Thirty-eight (35.2%) women underwent imaging following autologous fat grafting. Imaging was unremarkable in 17 (15.7%) patients, and non-suspicious imaging lesions were identified in 13 (12%) patients. Suspicious imaging lesions were discovered in 4 (3.7%) patients, and clinically palpable lesions were also detected in 4 (3.7%) patients. All 8 patients underwent biopsies (4 core and 4 excisional),all showing only fat necrosis. One (0.9%) local complication, a wound infection requiring oral antibiotics, was reported. There were no systemic complications. During this limited follow up period, no study patients had locoregional cancer recurrence. Conclusions:Autologous fat grafting in conjunction with breast reconstruction resulted in a biopsy rate of 7.4%, with no cases of locoregional recurrence observed. Based on these preliminary findings, autologous fat grafting appears to be a relatively safe procedure for refinement of the reconstructed breast in post-mastectomy patients.
    Plastic and reconstructive surgery. 10/2014; 134(4S-1 Suppl):86-87.
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    ABSTRACT: Objective: Nonvascularized partial skeletal muscle grafts are notorious for their limited force-generating capacity and tendency to degenerate in the absence of reinnervation. Accompanied by peripheral nerve implantation, however, partial muscle grafts can survive and transmit detectable electromyographic (EMG) signals capable of prosthetic control. Our study investigated partial muscle graft survival in the construction of regenerative peripheral nerve interfaces (RPNIs) and further characterized their electrophysiological properties across various muscle donor sites. Methods: Twenty F344 rats were assigned to 1 of 5 groups based on muscle graft type used for RPNI construction: 1) control-whole extensor digitorum longus; 2) partial biceps femoris; 3) partial rectus femoris; 4) partial lateral gastrocnemius; and 5) partial vastus medialis. Each graft (approximately 140-mg at initial harvest) was fixed to the femur, wrapped in small intestinal submucosa for tissue isolation, and implanted with the transected common peroneal nerve. After 4 months of recovery, in situ EMG and force testing were performed [Figure 1]. Results: All control RPNIs (n=4) transmitted detectable EMG signals, compared to 75% of partial muscle RPNIs (n=12 of 16). Significant differences between control and partial muscle RPNIs included average mass [118-mg (SD 42) vs. 66-mg (SD 25)], EMG peak-to-peak amplitude [6.7-mV (SD 2.3) vs. 1.16-mV (SD 1.5)], and maximum tetanic force [500-mN (SD 615) vs. 137-mN (SD 152)] [Figure 2]. Amongst partial muscle groups, donor muscle was not a significant predictor of EMG amplitude after adjusting for final RPNI mass and length at 4 months. Conclusions: We report that partial muscle graft RPNIs transmit detectable EMG signals with a 75% success rate at 4 months. This proof of concept underscores the potential to develop and refine partial muscle graft-based interfaces to harness peripheral motor nerve signals for prosthetic control. While signal size remains favorable (i.e. 10-100 times larger than signals recorded directly from peripheral nerves), further studies are warranted for optimization of partial muscle graft regeneration and methods of signal acquisition. Acknowledgements: This work was supported by DARPA (N66001-11-C-4190), the Plastic Surgery Foundation, and the Frederick A. Coller Surgical Society.
    Plastic and reconstructive surgery. 10/2014; 134(4S-1 Suppl):55-56.
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    ABSTRACT: PURPOSE: Regenerative Peripheral Nerve Interfaces (RPNIs) transfer signals between an amputee's residual limb and motorized prostheses. RPNIs are surgically transferred autologous muscle neurotized by residual nerve fascicles. Implanted electrodes transduce electromyographic signals from the RPNIs. RPNI signals have been shown to control brief prosthetic movements; but, RPNI use during prolonged, activity has not been demonstrated. Our purpose was to measure both RPNI maximal signaling capacity and signaling during continuous, repetitive, submaximal use. METHODS: Rats were assigned to either RPNI (n=4) or Control (n=7) groups. For the RPNI group, the extensor digitorum longus (EDL) muscle was transferred to the thigh and neurotized by the transected peroneal nerve. Bipolar electrodes were secured to the EDL muscles in each group. Five months post-surgery, maximal compound muscle action potential (CMAP) and maximal contractile force were measured following peroneal nerve stimulation. A 20 minute intermittent activation protocol that fatigues normal muscle was administered. This submaximal force protocol totaled 720 repeats of muscle excitation, contraction, and relaxation (Fig 1). Short excitations were evoked by 300 milliseconds of stimulation each second repeated for 360 contractions. This was followed by long excitations evoked by 600 milliseconds of stimulation per second for another 360 contractions. After five minutes of rest, maximal excitation was again measured. RESULTS: A high correlation was verified between maximal CMAP and maximal contractile force, r=0.81, p < 0.01 indicating RPNI signaling. RPNI group CMAP was 32% and maximal force was 23% of Control group amplitudes. The RPNI group averaged 26% of maximal force during shorter contractions and 10% during longer contractions (Fig 2). The Control group maintained 28% and 23% of maximal force during short and long contractions. Following the repetitive activations and a five minute rest, RPNIs recovered maximal contractile signaling on average equaling 72% of their individual initial maximal force while Controls recovered 87% of their initial max force production. Conclusion: Though signals produced by the RPNIs were not as large as Controls, signaling from the RPNIs resisted fatigue during repetitive activation similarly to Control muscle. RPNIs also showed recovery of maximal signaling within five minutes of repeated contractions. All RPNI signals were in the millivolt or milliNewton range with sufficient information to control prostheses. Acknowledgements: Defense Advanced Research Projects Agency (DARPA) MTO Contract No. N66001-11-C-4190.
    Plastic and reconstructive surgery. 10/2014; 134(4S-1 Suppl):41-42.
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    ABSTRACT: Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein-mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3',5'-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury-exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.
    Science translational medicine 09/2014; 6(255):255ra132. · 10.76 Impact Factor
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    ABSTRACT: Patients with severe burns suffer functional, structural, and esthetic complications. It is important to explore reconstructive options given that no ideal treatment exists. Transfer of adipose and adipose-derived stem cells (ASCs) has been shown to improve healing in various models. The authors hypothesize that use of fat isografts and/or ASCs will improve healing in a mouse model of burn injury. Twenty 6 to 8 week old C57BL/6 male mice received a 30% surface area partial-thickness scald burn. Adipose tissue and ASCs from inguinal fat pads were harvested from a second group of C57BL/6 mice. Burned mice received 500 μ;l subcutaneous injection at burn site of 1) processed adipose, 2) ASCs, 3) mixed adipose (adipose and ASCs), or 4) sham (saline) injection (n = 5/group) on the first day postinjury. Mice were followed by serial photography until being killed at days 5 and 14. Wounds were assessed for burn depth and healing by hematoxylin and eosin (H&E) and immunohistochemistry. All treated groups showed improved healing over controls defined by decreased wound depth, area, and apoptotic activity. After 5 days, mice receiving ASCs or mixed adipose displayed a non-significant improvement in vascularization. No significant changes in proliferation were noted at 5 days. Adipose isografts improve some early markers of healing postburn injury. The authors demonstrate that addition of these grafts improves specific structural markers of healing. This improvement may be because of an increase in early wound vascularity postgraft. Further studies are needed to optimize use of fat or ASC grafts in acute and reconstructive surgery.
    Journal of burn care & research: official publication of the American Burn Association 09/2014; · 1.54 Impact Factor
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    ABSTRACT: The field of plastic surgery has been at the forefront of ideation and innovation. Surgeon scientists today continue to develop novel products that fulfill the needs of the medical community and patients. Part of this process requires the approval from various regulatory agencies and offices, including the U.S. Food and Drug Administration. Unfortunately, medical training does not include regulatory knowledge, and many surgeon scientists find the regulatory pathway and U.S. Food and Drug Administration perplexing, overly complicated, and insurmountable. The authors aim to clearly outline the path of the regulatory process as it pertains to the U.S. Food and Drug Administration and its various jurisdictions that may relate to the plastic surgeon.
    Plastic and reconstructive surgery. 09/2014; 134(3):559-569.
  • Jessica B Chang, Theodore A Kung, Paul S Cederna
    Annals of Plastic Surgery 08/2014; · 1.38 Impact Factor
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    ABSTRACT: Heterotopic Ossification (HO) is a common, debilitating complication of burns, traumatic brain injuries, and musculoskeletal trauma and surgery. While the exact mechanism of ectopic bone formation is unknown, mesenchymal stem cells (MSCs) capable of osteogenic differentiation are known to play an essential role. Interestingly, the prevalence of HO in the elderly population is low despite the high overall occurrence of musculoskeletal injury and orthopedic procedures. We hypothesized that a lower osteogenicity of MSCs would be associated with blunted HO formation in old compared to young mice. In vitro osteogenic differentiation of adipose-derived MSCs from old (18-20 months) and young (6-8 weeks) C57/BL6 mice was assessed, with or without preceding burn injury. In vivo studies were then performed using an Achilles tenotomy with concurrent burn injury HO model. HO formation was quantified using μCT scans, Raman spectroscopy, and histology. MSCs from young mice had more in vitro bone formation, up-regulation of bone formation pathways, and higher activation of Smad and NF-κB signaling following burn injury. This effect was absent or blunted in cells from old mice. In young mice, burn injury significantly increased HO formation, NF-κB activation, and osteoclast activity at the tenotomy site. This blunted, reactive osteogenic response in old mice follows trends seen clinically and may be related to differences in the ability to mount acute inflammatory responses. This unique characterization of heterotopic ossification and MSC osteogenic differentiation following inflammatory insult establishes differences between age populations and suggests potential pathways that could be targeted in the future with therapeutics.
    Stem cells and development. 08/2014;
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    ABSTRACT: Background Common peroneal nerve palsy leading to foot drop is difficult to manage and has historically been treated with extended bracing with expectant waiting for return of nerve function. Peroneal nerve exploration has traditionally been avoided except in cases of known traumatic or iatrogenic injury, with tendon transfers being performed in a delayed fashion after exhausting conservative treatment. We present a new strategy for management of foot drop with nerve exploration and concomitant tendon transfer.Method We retrospectively reviewed a series of 12 patients with peroneal nerve palsies that were treated with tendon transfer from 2005 to 2011. Of these patients, seven were treated with simultaneous peroneal nerve exploration and repair at the time of tendon transfer.ResultsPatients with both nerve repair and tendon transfer had superior functional results with active dorsiflexion in all patients, compared to dorsiflexion in 40 % of patients treated with tendon transfers alone. Additionally, 57 % of patients treated with nerve repair and tendon transfer were able to achieve enough function to return to running, compared to 20 % in patients with tendon transfer alone. No patient had full return of native motor function resulting in excessive dorsiflexion strength.Conclusion The results of our limited case series for this rare condition indicate that simultaneous nerve repair and tendon transfer showed no detrimental results and may provide improved function over tendon transfer alone.
    Journal of Orthopaedic Surgery and Research 08/2014; 9(1):67. · 1.01 Impact Factor
  • Plastic &amp Reconstructive Surgery 08/2014; 134(2):344e-6e. · 3.54 Impact Factor
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    ABSTRACT: High-fidelity volitional control of bioengineered prosthetic limbs with multiple degrees of freedom requires the implantation of multiple recording interfaces to detect independent control signals. However, interface utilization is complicated by interfering electrophysiological signals originating from surrounding muscles and nerves, leading to equivocal signal detection. We developed and validated a surgical model to characterize signal propagation through various biomaterials to identify insulating substrates for use in implantable interfaces. The identification of these insulating materials will facilitate the acquisition of noncontaminated prosthetic control signals, thus improving manipulation of advanced prosthetic limbs.
    Annals of Plastic Surgery 07/2014; · 1.38 Impact Factor
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    ABSTRACT: The U.S. Food and Drug Administration is the government agency responsible for oversight of the safety and efficacy of pharmaceuticals and devices, including biologics and devices that combine biologics with other materials. Within the U.S. Food and Drug Administration, the Center for Biologics Evaluation and Research is specifically responsible for the evaluation and approval of biological products. This department of the U.S. Food and Drug Administration has a series of mechanisms in place to aid researchers in the process of developing new biologics. This article outlines the study phases involved in developing new biologics and how the Center for Biologics Evaluation and Research and investigators can work together to facilitate this process. It also discusses issues specific to biologics that have been encountered in the past and that investigators should consider when developing and obtaining approval for new biologics. The equivalent center within the U.S. Food and Drug Administration for approving medical devices is the Center for Devices and Radiological Health. The equivalent process of development and approval of medical devices is similarly discussed. Finally, essential contacts for investigators within the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health are provided.
    Plastic &amp Reconstructive Surgery 06/2014; 133(6):1495-501. · 3.54 Impact Factor
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    ABSTRACT: The regenerative peripheral nerve interface is an internal interface for signal transduction with external electronics of prosthetic limbs; it consists of an electrode and a unit of free muscle that is neurotized by a transected residual peripheral nerve. Adding a conductive polymer coating on electrodes improves electrode conductivity. This study examines regenerative peripheral nerve interface tissue viability and signal fidelity in the presence of an implanted electrode coated or uncoated with a conductive polymer.
    Plastic and reconstructive surgery. 06/2014; 133(6):1380-94.
  • Plastic and reconstructive surgery 04/2014; 133(4 Suppl):1015. · 2.74 Impact Factor
  • Plastic and reconstructive surgery 04/2014; 133(4 Suppl):1012-3. · 2.74 Impact Factor
  • Jessica B Chang, Theodore A Kung, Paul S Cederna
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    ABSTRACT: Marjolin's ulcers are rare cutaneous malignancies that most commonly present as squamous cell carcinomas in previously injured, chronically inflamed, or scarred skin. Acute and chronic types have been distinguished by the length of latency; by definition, the acute type occurs within 12 months of injury whereas the chronic type appears over 12 months after injury. In this report, 3 cases of acute Marjolin's ulcers are described and questions are raised about the diagnosis of acute Marjolin's ulcer. Other than a discrepancy in lag time, it is unclear if there is any difference in clinical or histological characteristics or even prognosis between acute and chronic Marjolin's ulcers. In fact, the acute type may simply be a preemptive diagnosis that conveniently describes a carcinoma associated with a nonhealing wound and discovered within a short time span. Moreover, the rarity of the diagnosis and the relatively rapid rate of malignant degeneration from the inciting injury lead one to question whether the injury may have simply revealed or accelerated a previously existing occult cutaneous malignancy. With no definitive clinical, histological, or prognostic distinction between acute and chronic Marjolin's ulcers, the use of such terminology may not benefit a clinician's understanding or practice. In fact, it merely supports the clinical guideline that any nonhealing wound, acute or chronic, should be biopsied and sent for pathologic examination to ensure that it does not represent a Marjolin's ulcer.
    Annals of plastic surgery 03/2014; · 1.29 Impact Factor

Publication Stats

928 Citations
257.17 Total Impact Points

Institutions

  • 1999–2014
    • University of Michigan
      • • Department of Surgery
      • • Section of Plastic and Reconstructive Surgery
      • • Department of Obstetrics and Gynecology
      • • Department of Biomedical Engineering
      Ann Arbor, Michigan, United States
  • 2013
    • Southern Illinois University Carbondale
      Illinois, United States
    • Michigan State University
      East Lansing, Michigan, United States
  • 2000–2013
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2012
    • Pennsylvania State University
      • Department of Bioengineering
      University Park, MD, United States
  • 2005–2007
    • Washington University in St. Louis
      • Division of Plastic Surgery
      Saint Louis, MO, United States
  • 2004
    • Duke University
      Durham, North Carolina, United States
  • 1999–2002
    • The University of Tokyo
      • Department of Plastic, Reconstructive and Aesthetic Surgery
      Tokyo, Tokyo-to, Japan
  • 2001
    • Duke University Medical Center
      Durham, North Carolina, United States