Publications by authors named "Michael T Chung"

67 Publications

E-Cigarette Burns and Explosions: What are the Patterns of Oromaxillofacial Injury?

J Oral Maxillofac Surg 2021 Mar 29. Epub 2021 Mar 29.

William Beaumont Hospital - Royal Oak, Department of Otolaryngology, Royal Oak, MI.

Purpose: With the recent increase in popularity of electronic cigarette use in the United States, its harmful effects are not only limited to smoke inhalation, but also to the possibility of e-cigarette device malfunction. The purpose of this review is to characterize oromaxillofacial trauma secondary to electronic cigarette device explosion.

Methods: For this systematic review, PubMed and Embase were searched in October 2019 using the following search terms: e-cigarette burns, e-cigarette injury, and e-cigarette explosions, which yielded 400 studies. Basic science research, animal studies, non-English studies, and reports of non-oromaxillofacial injuries were excluded. Study subject demographics, mechanism of trauma, injury type, treatment, and sequelae were recorded and analyzed.

Results: Of all studies, 20 studies met inclusion criteria, including 14 case reports and 6 case series, with a total of 21 study subjects. For cases that reported sex, 100% were male (20) with a mean age of 29.5 years. Most common lacerations and/or burns involved the lips (10/21), tongue (8/21), soft palate and/or hard palate (4/21), and nose (5/21). Thirteen subjects underwent surgeries including oral-maxillofacial surgery or dental implants (7/13), bone graft repair (3/13), open reduction and internal fixation for preservation of sinus outflow tracts (2/13), foreign body removal from the cervical spine (1/13), and iridectomy (1/13). Reported complications included bone loss secondary to traumatic fracture, tinnitus and hearing loss, lip paralysis secondary to persistent edema, major depressive disorder/ post-traumatic stress disorder, persistent sinusitis, photophobia, and bilateral axillary and hand contractures.

Conclusions: Electronic cigarette device malfunction and explosion carries great risk for acute oromaxillofacial trauma that may be disfiguring. With the increasing popularity of electronic cigarette use, clinicians and patients should be advised regarding dangers of electronic cigarette use.
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http://dx.doi.org/10.1016/j.joms.2021.03.008DOI Listing
March 2021

Using telemedicine to facilitate social distancing in otolaryngology: A systematic review.

J Telemed Telecare 2021 Feb 3:1357633X20985391. Epub 2021 Feb 3.

Department of Otolaryngology-Head and Neck Surgery, Karmanos Cancer Institute & Wayne State University, USA.

Objectives: As the coronavirus 2019 pandemic puts strains on current models of otolaryngology practice, telemedicine is an attractive way for otolaryngologists to reduce in-person appointments while still addressing the health of their patients. This systematic review of the literature aims to identify the evidence basis for using telemedicine in otolaryngology practice to limit person-to-person interactions while achieving comparable quality to in-person services.

Methods: The authors gathered articles from three databases (Embase, PubMed and Web of Science), performed a comprehensive literature review of articles published on telemedicine since 2002, and selected articles for inclusion based on their relevance to otolaryngology and the potential of the intervention to improve patient social distancing.

Results: A total of 7153 articles were identified from the initial query. After review, 35 met the inclusion criteria. Of the included articles, 32 (91%), found their specific telemedicine intervention to be effective when compared to in-person services. Twenty articles (57%) were related to remote otoscopy. Other telemedical interventions included videoconferencing for peri-operative visits, diagnosis of peritonsillar abscess, telephone-based voice evaluations and evaluation of nasal fractures.

Conclusions: Video-otoscopy is the most well-supported telemedical intervention which limits physical contact between otolaryngologists and their patients. Other interventions have also demonstrated efficacy but have yet to be as widely validated as video-otoscopy. Telehealth facilitators play a key role in providing high-quality telehealth services. More invasive procedures, such as laryngoscopy, require further evidence to demonstrate definite benefits in a telemedicine setting.
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http://dx.doi.org/10.1177/1357633X20985391DOI Listing
February 2021

Telemedicine in International Cleft Care: A Systematic Review.

Cleft Palate Craniofac J 2021 Feb 4:1055665621989140. Epub 2021 Feb 4.

12267Wayne State University School of Medicine, Detroit, MI, USA.

Background: Cleft lip and cleft palate (CLP) are among the world's most common congenital malformation and has a higher prevalence in developing nations due to environmental and genetic factors. Global efforts have been developed in order to prevent and treat the malformation. Telemedicine has been implemented in various humanitarian global missions with success and is currently the primary means of care due to COVID-19.

Objective: To assess the benefits and barriers of telehealth in the care of patients with CLP through a global approach.

Methods: Systematic review of the PubMed and Cochrane Review databases with relevant terms related to telemedicine in cleft lip and palate surgery.

Results: Eight articles fit the inclusion criteria and suggested benefits with the use of telemedicine in regard to education, preoperative, and postoperative care as well as increased access to underserved populations. Barriers included connectivity and accessibility concerns.

Conclusion: Telehealth is a beneficial way to evaluate patients with CLP in developing countries with proper care and follow-up to reduce complications and to improve health outcomes.
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http://dx.doi.org/10.1177/1055665621989140DOI Listing
February 2021

Functional Reconstruction of Forehead and Midface Deficits Using the Endoscopic Technique and Bio-Absorbable Implants.

Plast Surg (Oakv) 2020 Aug 18;28(3):142-147. Epub 2020 Feb 18.

Division of Facial Plastic Surgery, Department of Otolaryngology, Wayne State University, Detroit, MI, USA.

Objectives: Functional deficits of the forehead and midface can pose significant problems for patients varying from mild asymmetry to various degrees of functional impairment including total paralysis. Our objectives were to analyse the use of bio-absorbable implants to reconstruct forehead and midface deficits, all of which were for functional (noncosmetic) reasons.

Methods: This study was a retrospective case series between 2008 and 2018. Institutional review board approval was obtained from the Beaumont Health Human Investigation Committee. Surgeries were performed at a tertiary care centre. We evaluated 50 patients who underwent correction of functional deficits of forehead, eyebrow, and midface using the endoscopic technique and bio-absorbable implants. Patient demographics and indicated etiologies and characterization of minor and major complications and their occurrence rates were characterized.

Results: Fifty patients were included in the study from 2008 to 2018, with 68% female and 32% male. Combined blepharoplasty and brow lift was the most commonly performed procedure, followed by midface lift and browplasty. The mean follow-up time was 372 days. No major operative complications including stroke, permanent nerve paralysis, or mortality occurred. There was a 4% rate of temporary nerve paresthesia that resolved, 2% rate of infection, and 6% rate of implant migration requiring revision surgery.

Conclusion: The endoscopic approach and use of bio-absorbable implants to reconstruct functional deficits of the forehead and midface are safe and effective. There were zero major complications and most of the minor complications were temporary. There was a significant association between non-age-related functional impairment and risk of complication.
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http://dx.doi.org/10.1177/2292550320903401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436844PMC
August 2020

The impact of the COVID-19 pandemic on fellowship training: A national survey of pediatric otolaryngology fellowship directors.

Int J Pediatr Otorhinolaryngol 2020 Sep 23;136:110217. Epub 2020 Jun 23.

Wayne State University, Department of Otolaryngology, Detroit, MI, USA.

Objectives: To gain a better understanding of the effects the COVID-19 pandemic has had on current and future pediatric otolaryngology fellowship training, as well as how the application process was impacted this past year.

Methods: An anonymous web-based survey consisting of 24 questions was sent to all fellowship directors. The survey questions were designed to gain a better understanding of the effects of the current COVID-19 pandemic on the surgical and clinical experience of current, to characterize the types of supplemental educational experiences that fellowship directors had incorporated into the curriculum to compensate for the decreased surgical and clinical workload, and highlight differences based on geographic location.

Results: Overall, 22 of 36 fellowship directors responded to our survey, for a total response rate of 61%. The Midwest had the highest response rate at 72.7%, followed by the Northeast (71.4%), the West (50%), and the South (50%). The vast majority of fellowship directors (77.2%) reported the COVID-19 pandemic had a "significant impact" on overall pediatric otolaryngology fellowship training. 86.3% of fellowship directors reported that their programs were still performing some surgical operations, but with decreased overall volume. Interestingly, 13.6% of fellowship directors reported that their fellows had been pulled to medicine or ICU services to assist with the COVID-19 pandemic. Of these programs that had a fellow pulled to the ICU or medicine service, 2 out of 3 were located in the Northeast, with the remaining fellow being from a program in the South.

Conclusion: Overall, pediatric otolaryngology fellowship directors reported the COVID-19 pandemic has had a significant impact on the overall fellowship experience within the field of pediatric otolaryngology, with the majority feeling that both their fellows surgical and clinical experience have been significantly impacted.
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http://dx.doi.org/10.1016/j.ijporl.2020.110217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308764PMC
September 2020

Factors Important in the Selection of a Rhinology/Skull Base Surgery Fellow: A National Survey of Fellowship Directors.

Am J Rhinol Allergy 2021 Mar 10;35(2):234-238. Epub 2020 Aug 10.

Department of Otolaryngology, Wayne State University, Detroit, Michigan.

Background: The numbers of Rhinology/Skull Base Surgery fellowship programs and applicants have been increasing in recent years. However, little information is currently available with regards to the most important aspects of the application process.

Objective: The goal of this study was to determine the factors that Rhinology/Skull Base Surgery fellowship directors consider most important when selecting a fellow.

Methods: An anonymous, online survey was distributed to current Rhinology/Skull Base Surgery fellowship directors. 28 of 31 fellowship directors (90%) completed the survey. Respondents were asked to provide basic information regarding the program and to rank various selection factors they deem most important.

Results: For assessing the quality of an application, fellowship directors placed the highest value on LORs. Research experience and publications were also important considerations. The traditional strength of an applicant's residency program was a factor, while medical school performance, USMLE scores, and OTE score did not play a significant role in the selection process. For subjective assessment of applicants, the most value was placed on faculty assessment of the applicant during their interview. Attention was also given to personality fit with the program and the perceived maturity and initiative of the applicant.

Conclusion: Numerous academic achievements and personal characteristics are given consideration in the Rhinology/Skull Base Surgery fellowship selection process, but recommendation from a trusted colleague and performance on interviews were viewed to be the most critical factors for fellowship programs in selecting applicants. This is consistent with studies that have explored the selection process for other otolaryngology fellowship programs.
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http://dx.doi.org/10.1177/1945892420948778DOI Listing
March 2021

Novel Changes in Resident Education during a Pandemic: Strategies and Approaches to Maximize Residency Education and Safety.

Int Arch Otorhinolaryngol 2020 Jul 31;24(3):e267-e271. Epub 2020 Jul 31.

Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, United States.

 The COVID-19 pandemic has led to a reduction in surgical and clinical volume, which has altered the traditional training experience of the otolaryngology resident.  To describe the strategies we utilized to maximize resident education as well as ensure patient and staff safety during the pandemic.  We developed a system that emphasized three key elements. First and foremost, patient care remained the core priority. Next, clinical duties were restructured to avoid unnecessary exposure of residents. The third component was ensuring continuation of resident education and maximizing learning experiences.  To implement these key elements, our residency divided up our five hospitals into three functional groups based on geographical location and clinical volume. Each team works for three days at their assigned location before being replaced by the next three-person team at our two busiest sites. Resident teams are kept completely separate from each other, so that they do not interact with those working at other sites.  Despite the daily challenges encountered as we navigate through the COVID-19 pandemic, our otolaryngology residency program has been able to establish a suitable balance between maintenance of resident safety and well-being without compromise to patient care.
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http://dx.doi.org/10.1055/s-0040-1714147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394620PMC
July 2020

Fellow selection protocols in sleep surgery: a national survey of sleep surgery program directors.

Sleep Breath 2021 Mar 19;25(1):361-364. Epub 2020 Jun 19.

Department of Otolaryngology - Head and Neck Surgery, Wayne State University, Detroit, MI, USA.

Purpose: To determine the factors that sleep medicine/surgery fellowship program directors look for in applicants.

Methods: Program directors from 9 sleep medicine/surgery fellowship programs in the USA were sent an anonymous online survey. They were asked to select the five most important academic factors (of a list of 17) when evaluating potential fellowship candidates, then rank those five in order of importance. They were then asked to do the same for the most important subjective criteria (of a list of 12).

Results: Eight of 10 survey responses met inclusion criteria. Of the academic factors, strength of letters of recommendation, reputation of letter writer, and letters from sleep surgeons ranked highest. As for the subjective criteria, faculty assessment of the applicant on interview was ranked highest, followed by initiative and personality "fit" with the program. The reputation of an applicant's residency was ranked as more important than the reputation of their medical school. An applicant's performance in residency was assessed as more predictive of their performance in fellowship than performance during the interview process or position on the rank order list for the match. Only one program has a United States Medical Licensing Examination (USMLE) Step, and a different program has an Otolaryngology Training Examination (OTE) score cutoff.

Conclusion: Letters of recommendation and interview are the most important factors in the selection process for hybrid sleep medicine and surgery fellowship programs, followed by research and residency program reputation. Sleep surgery-specific experience is helpful.
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http://dx.doi.org/10.1007/s11325-020-02132-yDOI Listing
March 2021

Surgical Adjuncts to Rhinoplasty: An Algorithmic Approach.

Aesthetic Plast Surg 2020 10 7;44(5):1694-1704. Epub 2020 May 7.

Division of Plastic and Reconstructive Surgery, University of Kentucky, Lexington, KY, USA.

Background: Nasal aesthetics can be significantly affected by the interdependence of the surrounding bone and soft tissues of the face. These include the maxilla, septum, frontal bone, mandible, and the soft tissues and cartilage surrounding the nose. Therefore, it is pertinent to analyze and address these critical relationships of the nose in order to achieve a successful rhinoplasty. This work seeks to describe the battery of adjunct procedures available to supplement a rhinoplasty. Furthermore, each preoperative finding or indication for the adjunct is described in an algorithmic fashion.

Methods: A literature search using PubMed, Google Scholar, and a university library database was performed to locate papers describing adjunctive procedures to rhinoplasty. Indications and preoperative analysis were extracted from each paper. If the indication or finding was unclear, supplementary literature describing rhinoplasty and adjunctive analysis were sought in order to supplement our findings.

Results: Sixteen papers in total described adjunctive procedures for rhinoplasty. Each work highlighted a procedure or set of procedures on a surrounding facial feature including the forehead, brow, cheeks, lips, and chin, and neck. In total, 13 adjunct procedures for rhinoplasty are described with their respective indications. Additional literature and techniques were researched to clarify indicated procedures.

Conclusion: The ability to correctly understand the critical relationships of the nose can help the surgeon correctly recognize the indication for a rhinoplasty adjunct procedure, leading to better aesthetic balance and surgical outcomes.

Level Of Evidence Ii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-020-01744-9DOI Listing
October 2020

Head and neck fracture patterns associated with playground equipment use in the pediatric population.

Int J Pediatr Otorhinolaryngol 2020 07 1;134:110031. Epub 2020 Apr 1.

Wayne State University, Department of Otolaryngology, Detroit, MI, USA.

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http://dx.doi.org/10.1016/j.ijporl.2020.110031DOI Listing
July 2020

Fellow Selection Protocols in Facial Plastic Surgery: A National Survey of Facial Plastic Surgery Program Directors.

Facial Plast Surg Aesthet Med 2020 Jul/Aug;22(4):309-311. Epub 2020 Apr 8.

Division of Facial Plastic Surgery, Department of Otolaryngology, Wayne State University, Detroit, Michigan, USA.

Despite its popularity among otolaryngology residents, there is currently a paucity of knowledge on the match in facial plastics surgery fellowships and the selection criteria that drive the match process. To increase the understanding of this process and to improve the manner in which candidates are vetted, a survey study was designed. A 24-question online survey was designed to discern desired qualities regarding fellow selection, interview processes, fellow participation, and program director satisfaction with the current process. This survey was sent to all American Academy of Facial Plastic and Reconstructive Surgery fellowship program directors in the United States. Overall, 40 of the 64 fellowship directors responded to the survey for a total response rate of 62.5%. Most fellowship directors reported that the reputation of an applicant's residency was an important component of the selection criteria with 34 of 40 of those who responded rating it at least "somewhat important." With regard to the otolaryngology trainee examination, nearly all fellowship directors (39/40) reported that there was no minimum cutoff score to be offered an interview. When fellowship directors were asked to rank the academic components of an application that they viewed as most important, they most commonly reported that the strength of an applicant's letters of recommendation were most important. With the increasing popularity of fellowships within the field of otolaryngology, having an understanding of which components of the application process are viewed as most important by fellowship directors is crucial in applicants matching into the fellowship of their choice.
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http://dx.doi.org/10.1089/fpsam.2020.0085DOI Listing
November 2020

Global trends of hand and wrist trauma: a systematic analysis of fracture and digit amputation using the Global Burden of Disease 2017 Study.

Inj Prev 2020 10 13;26(Supp 1):i115-i124. Epub 2020 Mar 13.

Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, USA.

Background: As global rates of mortality decrease, rates of non-fatal injury have increased, particularly in low Socio-demographic Index (SDI) nations. We hypothesised this global pattern of non-fatal injury would be demonstrated in regard to bony hand and wrist trauma over the 27-year study period.

Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 was used to estimate prevalence, age-standardised incidence and years lived with disability for hand trauma in 195 countries from 1990 to 2017. Individual injuries included hand and wrist fractures, thumb amputations and non-thumb digit amputations.

Results: The global incidence of hand trauma has only modestly decreased since 1990. In 2017, the age-standardised incidence of hand and wrist fractures was 179 per 100 000 (95% uncertainty interval (UI) 146 to 217), whereas the less common injuries of thumb and non-thumb digit amputation were 24 (95% UI 17 to 34) and 56 (95% UI 43 to 74) per 100 000, respectively. Rates of injury vary greatly by region, and improvements have not been equally distributed. The highest burden of hand trauma is currently reported in high SDI countries. However, low-middle and middle SDI countries have increasing rates of hand trauma by as much at 25%.

Conclusions: Certain regions are noted to have high rates of hand trauma over the study period. Low-middle and middle SDI countries, however, have demonstrated increasing rates of fracture and amputation over the last 27 years. This trend is concerning as access to quality and subspecialised surgical hand care is often limiting in these resource-limited regions.
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http://dx.doi.org/10.1136/injuryprev-2019-043495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571361PMC
October 2020

Wounds Inhibit Tumor Growth In Vivo.

Ann Surg 2021 01;273(1):173-180

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

Objective: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo.

Summary Of Background Data: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo.

Methods: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells.

Results: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds.

Conclusion: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.
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http://dx.doi.org/10.1097/SLA.0000000000003255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169436PMC
January 2021

Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and Reactivation.

Stem Cells 2019 06 14;37(6):766-778. Epub 2019 Mar 14.

School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-β activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment ("drug on"), the impact of drug withdrawal ("drug off") implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment ("drug on") and subsequent withdrawal ("drug off") through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.
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http://dx.doi.org/10.1002/stem.2991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542699PMC
June 2019

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Am J Pathol 2018 11 22;188(11):2464-2473. Epub 2018 Aug 22.

Burn/Wound and Regenerative Medicine Laboratory, Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating populations have to HO. A shared circulation was obtained using a parabiosis model, established between an enhanced green fluorescent protein-positive/luciferase donor and a same-strain nonreporter recipient mouse. The nonreporter mouse received Achilles tendon transection and dorsal burn injury to induce HO formation. Bioluminescence imaging and immunostaining were performed to define the circulatory contribution of immune and mesenchymal cell populations. Histologic analysis showed circulating cells present throughout each stage of the developing HO anlagen. Circulating cells were present at the injury site during the inflammatory phase and proliferative period, with diminished contribution in mature HO. Immunostaining demonstrated that most early circulatory cells were from the innate immune system; only a small population of mesenchymal cells were present in the HO. We demonstrate the time course of the participation of circulatory cells in trauma-induced HO and identify populations of circulating cells present in different stages of HO. These findings further elucidate the relative contribution of local and systemic cell populations to HO.
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http://dx.doi.org/10.1016/j.ajpath.2018.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222270PMC
November 2018

PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing.

Plast Reconstr Surg 2018 01;141(1):55e-67e

Stanford, San Diego, and San Francisco, Calif.; Portland, Ore.; and New York, N.Y.

Background: Cell therapy with mesenchymal stromal cells is a promising strategy for tissue repair. Restoration of blood flow to ischemic tissues is a key step in wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) superfamily, consisting of transcription factors targeted for degradation by prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the proangiogenic capability of mesenchymal stromal cells and to use these modified cells to promote wound healing.

Methods: Mesenchymal stromal cells harvested from mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; control cells were transduced with scrambled shRNA (shScramble) construct. Gene expression quantification, human umbilical vein endothelial cell tube formation assays, and wound healing assays were used to assess the effect of PHD knockdown mesenchymal stromal cells on wound healing dynamics.

Results: PHD-2 knockdown mesenchymal stromal cells overexpressed HIF-1α and multiple angiogenic factors compared to control (p < 0.05). Human umbilical vein endothelial cells treated with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited increased formation of capillary-like structures and enhanced migration compared with human umbilical vein endothelial cells treated with conditioned medium from shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 0.05). Histologic studies revealed increased blood vessel density and increased cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells (p < 0.05).

Conclusions: Silencing PHD-2 in mesenchymal stromal cells augments their proangiogenic potential in wound healing therapy. This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors.
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http://dx.doi.org/10.1097/PRS.0000000000003959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747314PMC
January 2018

Heterotopic ossification and the elucidation of pathologic differentiation.

Bone 2018 04 5;109:12-21. Epub 2017 Oct 5.

Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address:

Tissue regeneration following acute or persistent inflammation can manifest a spectrum of phenotypes ranging from the adaptive to the pathologic. Heterotopic Ossification (HO), the endochondral formation of bone within soft-tissue structures following severe injury serves as a prominent example of pathologic differentiation; and remains a persistent clinical issue incurring significant patient morbidity and expense to adequately diagnose and treat. The pathogenesis of HO provides an intriguing opportunity to better characterize the cellular and cell-signaling contributors to aberrant differentiation. Indeed, recent work has continued to resolve the unique cellular lineages, and causative pathways responsible for ectopic bone development yielding promising avenues for the development of novel therapeutic strategies shown to be successful in analogous animal models of HO development. This review details advances in the understanding of HO in the context of inciting inflammation, and explains how these advances inform the current standards of diagnosis and treatment.
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http://dx.doi.org/10.1016/j.bone.2017.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585944PMC
April 2018

Evaluation of Salivary Cytokines for Diagnosis of both Trauma-Induced and Genetic Heterotopic Ossification.

Front Endocrinol (Lausanne) 2017 24;8:74. Epub 2017 Apr 24.

Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Purpose: Heterotopic ossification (HO) occurs in the setting of persistent systemic inflammation. The identification of reliable biomarkers can serve as an early diagnostic tool for HO, especially given the current lack of effective treatment strategies. Although serum biomarkers have great utility, they can be inappropriate or ineffective in traumatic acute injuries and in patients with fibrodysplasia ossificans progressiva (FOP). Therefore, the goal of this study is to profile the cytokines associated with HO using a different non-invasive source of biomarkers.

Methods: Serum and saliva were collected from a model of trauma-induced HO (tHO) with hind limb Achilles' tenotomy and dorsal burn injury at indicated time points (pre-injury, 48 h, 1 week, and 3 weeks post-injury) and a genetic non-trauma HO model ( ). Samples were analyzed for 27 cytokines using the Bio-Plex assay. Histologic evaluation was performed in mice and at 48 h and 1 week post-injury in burn tenotomy mice. The mRNA expression levels of these cytokines at the tenotomy site were also quantified with quantitative real-time PCR. Pearson correlation coefficient was assessed between saliva and serum.

Results: Levels of TNF-α and IL-1β peaked at 48 h and 1 week post-injury in the burn/tenotomy cohort, and these values were significantly higher when compared with both uninjured ( < 0.01,  < 0.03) and burn-only mice ( < 0.01,  < 0.01). Immunofluorescence staining confirmed enhanced expression of IL-1β, TNF-α, and MCP-1 at the tenotomy site 48 h after injury. Monocyte chemoattractant protein-1 (MCP-1) and VEGF was detected in saliva showing elevated levels at 1 week post-injury in our tHO model when compared with both uninjured ( < 0.001,  < 0.01) and burn-only mice ( < 0.005,  < 0.01). The Pearson correlation between serum MCP-1 and salivary MCP-1 was statistically significant ( = 0.9686,  < 0.001) Similarly, the Pearson correlation between serum VEGF and salivary VEGF was statistically significant ( = 0.9709,  < 0.05).

Conclusion: In this preliminary study, we characterized the diagnostic potential of specific salivary cytokines that may serve as biomarkers for an early-stage diagnosis of HO. This study identified two candidate biomarkers for further study and suggests a novel method for diagnosis in the context of current difficult diagnosis and risks of current diagnostic methods in certain patients.
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http://dx.doi.org/10.3389/fendo.2017.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401868PMC
April 2017

Combined reflectance and Raman spectroscopy to assess degree of in vivo angiogenesis after tissue injury.

J Surg Res 2017 03 19;209:174-177. Epub 2016 Sep 19.

Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: Angiogenesis, the formation of blood vessels, is a critical aspect of wound healing. Disorders of wound healing are often characterized by lack of angiogenesis, a condition frequently observed in aging and diabetic patients. Current techniques for assessing blood at injury sites are limited to contrast-imaging, including angiography. However, these techniques do not directly observe oxygenation of blood and are not amenable to serial evaluation. A multimodal noninvasive reflectance and Raman spectrometer have been proposed to help clinicians as a point-of-care tool to interrogate local angiogenesis and tissue architecture, respectively. The spectrometer system is a rapid, noninvasive, and label-free technology well-suited for the clinical environment.

Materials And Methods: To demonstrate feasibility, the spectrometer system was used to interrogate angiogenesis serially over 9 wk as a result of heterotopic ossification (HO) development in a validated murine model. End-stage HO was confirmed by micro-computed tomography.

Results: Our preliminary results suggest that reflectance spectroscopy can be used to delineate vessel formation and that pathologic wounds may be characterized by unique spectra. In our model, HO formed at sites 1-3, whereas sites 4 and 5 did not have radiographic evidence of HO.

Conclusions: A point-of-care system like that demonstrated here shows potential as a noninvasive tool to assess local angiogenesis and tissue architecture that may allow for timely intervention in a clinical setting.
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http://dx.doi.org/10.1016/j.jss.2016.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536340PMC
March 2017

mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration.

JCI Insight 2016 12 8;1(20):e89805. Epub 2016 Dec 8.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysplasia ossificans progressiva (FOP), or patients with surgically placed BMP implants for bone healing. We use a genetic mouse model of hyperactive BMP signaling to show the development of intramuscular fibrosis surrounding areas of ectopic bone following muscle injury. Rapamycin, which we have previously shown to eliminate ectopic ossification in this model, also eliminates fibrosis without reducing osteogenic differentiation, suggesting clinical value for patients with FOP and with BMP implants. Finally, we use reporter mice to show that BMP signaling is positively associated with myofiber cross-sectional area. These findings underscore an approach in which 2 therapeutics (rapamycin and BMP ligand) can offset each other, leading to an improved outcome.
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http://dx.doi.org/10.1172/jci.insight.89805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135269PMC
December 2016

Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon.

Stem Cells 2017 03 8;35(3):705-710. Epub 2016 Nov 8.

Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.

The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomato ). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and coexpress markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult preinjury restricted cells coexpressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1 ), tendons and joints formed HO. Postnatal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1 ) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive BMP receptor (e.g., caACVR1) activity. Stem Cells 2017;35:705-710.
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http://dx.doi.org/10.1002/stem.2515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529170PMC
March 2017

A Novel Method of Human Adipose-Derived Stem Cell Isolation with Resultant Increased Cell Yield.

Plast Reconstr Surg 2016 Dec;138(6):983e-996e

Stanford, Calif.

Background: The authors have developed a novel protocol for isolating adipose-derived stem cells from human lipoaspirate. In this study, they compare their new method to a previously published standard protocol.

Methods: Human adipose-derived stem cell isolation was performed using two methods to compare cell yield, cell viability, cell proliferation, and regenerative potential. The new and conventional isolation methods differ in two key areas: the collagenase digestion buffer constituents and the use of an orbital shaker. The osteogenic and adipogenic potential of adipose-derived stem cells isolated using both protocols was assessed in vitro, and gene expression analysis was performed. To assess the ability of the isolated cells to generate bone in vivo, the authors created critical-size calvarial defects in mice, which were treated with adipose-derived stem cells loaded onto hydroxyapatite-coated poly(lactic-co-glycolic acid) scaffolds. To test the ability of the isolated cells to enhance adipogenesis, the cells were added to lipoaspirate and placed beneath the scalp of immunocompromised mice. Fat graft volume retention was subsequently assessed by serial computed tomographic volumetric scanning.

Results: The new method resulted in a 10-fold increased yield of adipose-derived stem cells compared with the conventional method. Cells harvested using the new method demonstrated significantly increased cell viability and proliferation in vitro (p < 0.05). New method cells also demonstrated significantly enhanced osteogenic and adipogenic differentiation capacity in vitro (p < 0.05) in comparison with the conventional method cells. Both cell groups demonstrated equivalent osteogenic and adipogenic regenerative potential in mice.

Conclusions: The authors have developed a protocol that maximizes the yield of adipose-derived stem cells derived from lipoaspirate. The new method cells have increased osteogenic and adipogenic potential in vitro and are not inferior to conventional method cells in terms of their ability to generate bone and fat in vivo.

Clinical Question/level Of Evidence: Therapeutic, V.
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http://dx.doi.org/10.1097/PRS.0000000000002790DOI Listing
December 2016

Microfluidic single-cell transcriptional analysis rationally identifies novel surface marker profiles to enhance cell-based therapies.

Nat Commun 2016 06 21;7:11945. Epub 2016 Jun 21.

Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

Current progenitor cell therapies have only modest efficacy, which has limited their clinical adoption. This may be the result of a cellular heterogeneity that decreases the number of functional progenitors delivered to diseased tissue, and prevents correction of underlying pathologic cell population disruptions. Here, we develop a high-resolution method of identifying phenotypically distinct progenitor cell subpopulations via single-cell transcriptional analysis and advanced bioinformatics. When combined with high-throughput cell surface marker screening, this approach facilitates the rational selection of surface markers for prospective isolation of cell subpopulations with desired transcriptional profiles. We establish the usefulness of this platform in costly and highly morbid diabetic wounds by identifying a subpopulation of progenitor cells that is dysfunctional in the diabetic state, and normalizes diabetic wound healing rates following allogeneic application. We believe this work presents a logical framework for the development of targeted cell therapies that can be customized to any clinical application.
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http://dx.doi.org/10.1038/ncomms11945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512622PMC
June 2016

Facial Feminization: Systematic Review of the Literature.

Plast Reconstr Surg 2016 Jun;137(6):1759-1770

Seattle, Wash.; Lexington, Ky.; Loma Linda and San Francisco, Calif.; Ann Arbor, Mich.; and Durham, N.C.

Background: Facial feminization surgery encompasses a broad range of craniomaxillofacial surgical procedures designed to change masculine facial features into feminine features. The surgical principles of facial feminization surgery can be applied to male-to-female transsexuals and anyone desiring feminization of the face. Although the prevalence of these procedures is difficult to quantify, because of the rising prevalence of transgenderism (approximately one in 14,000 men) along with improved insurance coverage for gender-confirming surgery, surgeons versed in techniques, outcomes, and challenges of facial feminization surgery are needed. This review is designed to critically appraise the current facial feminization surgery literature.

Methods: A comprehensive literature search of the Medline, PubMed, and EMBASE databases was conducted for studies published through October of 2014 with multiple search terms related to facial feminization. Data on techniques, outcomes, complications, and patient satisfaction were collected.

Results: Fifteen articles were selected and reviewed from the 24 identified, all of which were either retrospective or case series/reports. Articles covered a variety of facial feminization procedures. A total of 1121 patients underwent facial feminization surgery, with seven complications reported, although many articles did not explicitly comment on complications. Satisfaction was high, although most studies did not use validated or quantified approaches to address satisfaction.

Conclusions: Facial feminization surgery appears to be safe and satisfactory for patients. Further studies are required to better compare different techniques to more robustly establish best practices. Prospective studies and patient-reported outcomes are needed to establish quality-of-life outcomes for patients. However, based on these studies, it appears that facial feminization surgery is highly efficacious and beneficial to patients.
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http://dx.doi.org/10.1097/PRS.0000000000002171DOI Listing
June 2016

Scaffold-mediated BMP-2 minicircle DNA delivery accelerated bone repair in a mouse critical-size calvarial defect model.

J Biomed Mater Res A 2016 08 3;104(8):2099-107. Epub 2016 Jun 3.

Department of Orthopaedic Surgery, Stanford University School of Medicine, Clark Center E-150, 300 Pasteur Drive, Edwards R105, MC5341, Stanford, California, 94305.

Scaffold-mediated gene delivery holds great promise for tissue regeneration. However, previous attempts to induce bone regeneration using scaffold-mediated non-viral gene delivery rarely resulted in satisfactory healing. We report a novel platform with sustained release of minicircle DNA (MC) from PLGA scaffolds to accelerate bone repair. MC was encapsulated inside PLGA scaffolds using supercritical CO2 , which showed prolonged release of MC. Skull-derived osteoblasts transfected with BMP-2 MC in vitro result in higher osteocalcin gene expression and mineralized bone formation. When implanted in a critical-size mouse calvarial defect, scaffolds containing luciferase MC lead to robust in situ protein production up to at least 60 days. Scaffold-mediated BMP-2 MC delivery leads to substantially accelerated bone repair as early as two weeks, which continues to progress over 12 weeks. This platform represents an efficient, long-term nonviral gene delivery system, and may be applicable for enhancing repair of a broad range of tissues types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2099-2107, 2016.
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http://dx.doi.org/10.1002/jbm.a.35735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127622PMC
August 2016

Winner of the Young Investigator Award of the Society for Biomaterials at the 10th World Biomaterials Congress, May 17-22, 2016, Montreal QC, Canada: Microribbon-based hydrogels accelerate stem cell-based bone regeneration in a mouse critical-size cranial defect model.

J Biomed Mater Res A 2016 06 9;104(6):1321-31. Epub 2016 Apr 9.

Department of Orthopaedic Surgery, Stanford University School of Medicine, 300 Pasteur Dr, Edward Building Room 114, Stanford, California 94305.

Stem cell-based therapies hold great promise for enhancing tissue regeneration. However, the majority of cells die shortly after transplantation, which greatly diminishes the efficacy of stem cell-based therapies. Poor cell engraftment and survival remain a major bottleneck to fully exploiting the power of stem cells for regenerative medicine. Biomaterials such as hydrogels can serve as artificial matrices to protect cells during delivery and guide desirable cell fates. However, conventional hydrogels often lack macroporosity, which restricts cell proliferation and delays matrix deposition. Here we report the use of injectable, macroporous microribbon (μRB) hydrogels as stem cell carriers for bone repair, which supports direct cell encapsulation into a macroporous scaffold with rapid spreading. When transplanted in a critical-sized, mouse cranial defect model, μRB-based hydrogels significantly enhanced the survival of transplanted adipose-derived stromal cells (ADSCs) (81%) and enabled up to three-fold cell proliferation after 7 days. In contrast, conventional hydrogels only led to 27% cell survival, which continued to decrease over time. MicroCT imaging showed μRBs enhanced and accelerated mineralized bone repair compared to hydrogels (61% vs. 34% by week 6), and stem cells were required for bone repair to occur. These results suggest that paracrine signaling of transplanted stem cells are responsible for the observed bone repair, and enhancing cell survival and proliferation using μRBs further promoted the paracrine-signaling effects of ADSCs for stimulating endogenous bone repair. We envision μRB-based scaffolds can be broadly useful as a novel scaffold for enhancing stem cell survival and regeneration of other tissue types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1321-1331, 2016.
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http://dx.doi.org/10.1002/jbm.a.35715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142823PMC
June 2016

Reply: Technology and Plastic Surgery: Potential Pitfalls for Patient Confidentiality and Proposed Solutions.

Plast Reconstr Surg 2016 Feb;137(2):485e-486e

Division of Plastic Surgery, Albany Medical Center, Albany, N.Y. Department of Plastic Surgery, Loma Linda University, Loma Linda, Calif. Division of Plastic and Reconstructive Surgery, Mount Sinai Hospital, New York, N.Y.

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http://dx.doi.org/10.1097/01.prs.0000475821.58283.47DOI Listing
February 2016

Reply: Vaginal Labiaplasty: Current Practices and a Simplified Classification System for Labial Protrusion.

Plast Reconstr Surg 2015 Dec;136(6):846e-847e

Department of Plastic Surgery, Loma Linda University, Loma Linda, Calif. Division of Plastic and Reconstructive Surgery, Mount Sinai Hospital, New York, N.Y. Miami Plastic Surgery, Miami, Fla. Division of Plastic Surgery, Albany Medical Center, Albany, N.Y.

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http://dx.doi.org/10.1097/PRS.0000000000001805DOI Listing
December 2015

Reply: Vaginal Labiaplasty: Current Practices and a Simplified Classification System for Labial Protrusion.

Plast Reconstr Surg 2015 Nov;136(5):706e-707e

Department of Plastic Surgery, Loma Linda University, Loma Linda, Calif. Miami Plastic Surgery, Miami, Fla. Division of Plastic and Reconstructive Surgery, Mount Sinai Hospital, New York, N.Y. Division of Plastic, Maxillofacial, and Oral Surgery, Duke University, Durham, N.C. Division of Plastic Surgery, Albany Medical Center, Albany, N.Y.

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http://dx.doi.org/10.1097/PRS.0000000000001666DOI Listing
November 2015