Bio

Clinical Focus


  • Residency

Honors & Awards


  • Thomas R. Russel Resident Research Award, Northern California Chapter American College of Surgeons (2018)
  • Child Health Research Institute Postdoctoral Support Grant, Stanford University School of Medicine (2016 - 2017)
  • Transplant and Tissue Engineering Center of Excellence Research Award, Stanford University School of Medicine (2016 - 2017)
  • Best Basic Science Presentation, Division of Plastic Surgery, Stanford University School of Medicine (2016)
  • Leadership and Advocacy Summit Resident Scholarship, American College of Surgeons (2016)
  • Hagey Research Fellow, Hagey Family Endowed Fund in Stem Cell Research and Regenerative Medicine, Stanford University School of Medicine (2015 - 2017)
  • Resident Research Scholarship, American College of Surgeons (2015 - 2017)
  • PGY2 Resident of the Year, Stanford University Department of Vascular Surgery (2015)
  • Weinstein Research Fellowship, Columbia University (2010)
  • Bachelor of Science awarded with Honors, Brown University (2008)
  • Undergraduate Teaching and Research Award, Brown University (2004)

Boards, Advisory Committees, Professional Organizations


  • Resident Member, Faculty Search Committee, Stanford University School of Medicine Division of Plastic Surgery (2017 - 2017)
  • Resident Member, Stanford Hospital Graduate Medical Education Task Force (2016 - Present)
  • Resident Liaison, American College of Surgeons, Northern California Chapter (2015 - Present)
  • Resident Member, Stanford Hospital ICU MD-RN Communication Task Force (2015 - 2017)
  • Resident Member, Association for Academic Surgery (2014 - Present)
  • Resident Member, American College of Surgeons (2013 - Present)

Professional Education


  • BS, Brown University, Biochemistry (2008)
  • MD, Columbia University (2013)

Research & Scholarship

Current Research and Scholarly Interests


Abdominal adhesions, skin scarring, fibrosis, wound healing.

Publications

All Publications


  • In Vitro and In Vivo Osteogenic Differentiation of Human Adipose-Derived Stromal Cells. Methods in molecular biology (Clifton, N.J.) Marshall, C. D., Brett, E. A., Moore, A. L., Wan, D. C., Longaker, M. T. 2019; 1891: 9–18

    Abstract

    Adipose-derived stromal cells (ASCs) are a promising population of cells that may be useful for the regeneration of human tissue defects. ASCs are capable of forming bone tissue in vitro and in vivo. Further work is required to determine the optimal conditions that will allow human ASCs to regenerate tissue in clinically significant tissue defects. Here we present three experimental protocols that are indispensable for the study of ASC osteogenic activity.

    View details for PubMedID 30414122

  • Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature Ransom, R. C., Carter, A. C., Salhotra, A., Leavitt, T., Marecic, O., Murphy, M. P., Lopez, M. L., Wei, Y., Marshall, C. D., Shen, E. Z., Jones, R. E., Sharir, A., Klein, O. D., Chan, C. K., Wan, D. C., Chang, H. Y., Longaker, M. T. 2018

    Abstract

    During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which isa process that is used in humans to correct an undersized lower jawthat involves surgically separating the jaw bone, whichelicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.

    View details for PubMedID 30356216

  • Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes (vol 9, 2971, 2018) NATURE COMMUNICATIONS Ransom, R. C., Foster, D. S., Salhotra, A., Jones, R., Marshall, C. D., Leavitt, T., Murphy, M. P., Moore, A. L., Blackshear, C. P., Brett, E. A., Wan, D. C., Longaker, M. T. 2018; 9
  • Implementing a Standardized Nurse-driven Rounding Protocol in a Trauma-surgical Intensive Care Unit: A Single Institution Experience. Cureus Marshall, C. D., Fay, M. E., Phillips, B., Faurote, R., Kustudia, J., Ransom, R. C., Henley, C., DiConstanzo, L., Jopling, J. K., Sang, A. X., Spain, D. A., Tisnado, J. A., Weiser, T. G. 2018; 10 (10): e3422

    Abstract

    Introduction Patient care in the trauma-surgical intensive care unit (SICU) requires trust and effective communication between nurses and physicians. Our SICU suffered from poor communication and trust between nurses and physicians, negatively impacting the working environment and, potentially, patient care. Methods A SICU Task Force studied communication practices and identified areas for improvement, leading to several interventions. The daily physician rounding was altered to improve communication and to enhance the role of the registered nurses (RN) inrounds. Additionally, a formal night resident rounding time was implemented. Results A post-intervention survey focusing on cooperation, teamwork, and appreciation between nurses and physicians revealed improvement in these domains. Informal feedback from nurses and physicians indicated improved working relationships and satisfaction with the SICU environment. However, results of a national survey performed after the intervention did not show the same level of improvement. Conclusions A Task Force consisting of SICU nurses and physicians can effectively study a widespread communication issue and implement targeted interventions. While informal feedback may indicate improvement, it can be difficult to demonstrate improvement using formal surveys.

    View details for DOI 10.7759/cureus.3422

    View details for PubMedID 30546974

  • Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes. Nature communications Ransom, R. C., Foster, D. S., Salhotra, A., Jones, R. E., Marshall, C. D., Leavitt, T., Murphy, M. P., Moore, A. L., Blackshear, C. P., Wan, D. C., Longaker, M. T. 2018; 9 (1): 2971

    Abstract

    Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through thepackaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreERT2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.

    View details for PubMedID 30061668

  • Cutaneous Scarring: Basic Science, Current Treatments, and Future Directions ADVANCES IN WOUND CARE Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Lorenz, H., Longaker, M. T. 2018; 7 (2): 29–45

    Abstract

    Significance: Scarring of the skin from burns, surgery, and injury constitutes a major burden on the healthcare system. Patients affected by major scars, particularly children, suffer from long-term functional and psychological problems. Recent Advances: Scarring in humans is the end result of the wound healing process, which has evolved to rapidly repair injuries. Wound healing and scar formation are well described on the cellular and molecular levels, but truly effective molecular or cell-based antiscarring treatments still do not exist. Recent discoveries have clarified the role of skin stem cells and fibroblasts in the regeneration of injuries and formation of scar. Critical Issues: It will be important to show that new advances in the stem cell and fibroblast biology of scarring can be translated into therapies that prevent and reduce scarring in humans without major side effects. Future Directions: Novel therapies involving the use of purified human cells as well as agents that target specific cells and modulate the immune response to injury are currently undergoing testing. In the basic science realm, researchers continue to refine our understanding of the role that particular cell types play in the development of scar.

    View details for PubMedID 29392092

    View details for PubMedCentralID PMC5792238

  • Recovery of a Missile Embolus From the Right Ventricle. Annals of thoracic surgery Marshall, C. D., Ma, M. R., Park, J., Sheckter, C. C., Massoudi, R. A., Ligman, C. M., Jou, R. M., Ogden, W. D. 2017; 103 (1): e69-e71

    Abstract

    Missile embolism is a clinical entity in which a projectile object enters a blood vessel and is carried to a distant part of the body. We present a case of the discovery of an iliac vein to right ventricle missile embolus in a young man, with successful extraction through a right atriotomy. We provide a historical overview of the literature concerning missile embolism, and we argue that whereas acute embolized projectiles should be removed in almost all cases, it may be reasonable to simply observe an asymptomatic chronic missile embolus.

    View details for DOI 10.1016/j.athoracsur.2016.06.107

    View details for PubMedID 28007279

  • Creation of Abdominal Adhesions in Mice JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Cheung, A. T., Malhotra, S., Lorenz, H. P., Longaker, M. T. 2016

    Abstract

    Abdominal adhesions consist of fibrotic tissue that forms in the peritoneal space in response to an inflammatory insult, typically surgery or intraabdominal infection. The precise mechanisms underlying adhesion formation are poorly understood. Many compounds and physical barriers have been tested for their ability to prevent adhesions after surgery with varying levels of success. The mouse and rat are important models for the study of abdominal adhesions. Several different techniques for the creation of adhesions in the mouse and rat exist in the literature. Here we describe a protocol utilizing abrasion of the cecum with sandpaper and sutures placed in the right abdominal sidewall. The mouse is anesthetized and the abdomen is prepped. A midline laparotomy is created and the cecum is identified. Sandpaper is used to gently abrade the surface of the cecum. Next, several figure-of-eight sutures are placed into the peritoneum of the right abdominal sidewall. The abdominal cavity is irrigated, a small amount of starch is applied, and the incision is closed. We have found that this technique produces the most consistent adhesions with the lowest mortality rate.

    View details for DOI 10.3791/54450

    View details for Web of Science ID 000391742700091

    View details for PubMedID 27685681

  • Wounds Inhibit Tumor Growth In Vivo. Annals of surgery Hu, M. S., Maan, Z. N., Leavitt, T., Hong, W. X., Rennert, R. C., Marshall, C. D., Borrelli, M. R., Zhu, T. N., Esquivel, M., Zimmermann, A., McArdle, A., Chung, M. T., Foster, D. S., Jones, R. E., Gurtner, G. C., Giaccia, A. J., Lorenz, H. P., Weissman, I. L., Longaker, M. T. 2019

    Abstract

    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.

    View details for PubMedID 30829705

  • Doxycycline Reduces Scar Thickness and Improves Collagen Architecture. Annals of surgery Moore, A. L., desJardins-Park, H. E., Duoto, B. A., Mascharak, S., Murphy, M. P., Irizarry, D. M., Foster, D. S., Jones, R. E., Barnes, L. A., Marshall, C. D., Ransom, R. C., Wernig, G., Longaker, M. T. 2018

    Abstract

    OBJECTIVE: To investigate the effects of local doxycycline administration on skin scarring.BACKGROUND: Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo.METHODS: Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue.RESULTS: A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005).CONCLUSIONS: Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.

    View details for PubMedID 30585822

  • Author Correction: Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes. Nature communications Ransom, R. C., Foster, D. S., Salhotra, A., Jones, R. E., Marshall, C. D., Leavitt, T., Murphy, M. P., Moore, A. L., Blackshear, C. P., Brett, E. A., Wan, D. C., Longaker, M. T. 2018; 9 (1): 4411

    Abstract

    In the original version of this Article, the authors inadvertently omitted Elizabeth A. Brett, who contributed to the generation of the histology figures, from the author list.This has now been corrected in both the PDF and HTML versions of the Article.

    View details for PubMedID 30341306

  • Engrailed1-Positive Fibroblasts May Modulate Transcription of the TGF-beta Pathway in the Transition from Scarless Healing to Scarring Phenotype Moore, A. L., Marshall, C. D., Des Jardins-Park, H. E., Duoto, B. A., Mascharak, S., Barnes, A., Ransom, R. C., Hu, M. S., Lorenz, H., Longaker, M. T. ELSEVIER SCIENCE INC. 2018: E221–E222
  • Acta2, Tnc, and Col24a1 Expression Are Associated with Abdominal Adhesion Formation Marshall, C. D., Foster, D. S., Ransom, R. C., Manjunath, A., Gulati, G., Hu, M. S., Moore, A. L., Barnes, L. A., Longaker, M. T. ELSEVIER SCIENCE INC. 2018: E128
  • Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation ADVANCES IN WOUND CARE Barnes, L. A., Marshall, C. D., Leavitt, T., Hu, M. S., Moore, A. L., Gonzalez, J. G., Longaker, M. T., Gurtner, G. C. 2018; 7 (2): 47–56

    Abstract

    Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.

    View details for PubMedID 29392093

    View details for PubMedCentralID PMC5792236

  • Prrx1 Labels the Fibrogenic Fibroblast in the Ventral Dermis Hu, M., Leavitt, T., Garcia, J., Ransom, R., Litzenburger, U., Walmsley, G., Marshall, C., Moore, A., Mascharak, S., Chan, C., Wan, D., Lorenz, P., Chang, H., Longaker, M. WILEY. 2018: A4
  • Scarless wound healing: Transitioning from fetal research to regenerative healing. Wiley interdisciplinary reviews. Developmental biology Moore, A. L., Marshall, C. D., Barnes, L. A., Murphy, M. P., Ransom, R. C., Longaker, M. T. 2018; 7 (2)

    Abstract

    Since the discovery of scarless fetal skin wound healing, research in the field has expanded significantly with the hopes of advancing the finding to adult human patients. There are several differences between fetal and adult skin that have been exploited to facilitate scarless healing in adults including growth factors, cytokines, and extracellular matrix substitutes. However, no one therapy, pathway, or cell subtype is sufficient to support scarless wound healing in adult skin. More recently, products that contain or mimic fetal and adult uninjured dermis were introduced to the wound healing market with promising clinical outcomes. Through our review of the major experimental targets of fetal wound healing, we hope to encourage research in areas that may have a significant clinical impact. Additionally, we will investigate therapies currently in clinical use and evaluate whether they represent a legitimate advance in regenerative medicine or a vulnerary agent. WIREs Dev Biol 2018, 7:e309. doi: 10.1002/wdev.309 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Plant Development > Cell Growth and Differentiation Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells.

    View details for PubMedID 29316315

  • Cellular Mechanisms Underlying Regeneration in Mandibular Distraction Osteogenesis Ransom, R. C., Leavitt, T., Murphy, M. P., Marecic, O., Lopez, M., Marshall, C. D., Barnes, L. A., Wan, D. C., Chan, C. K., Longaker, M. T. ELSEVIER SCIENCE INC. 2017: E143–E144
  • Epigenetic Analysis of Scar Forming Fibroblasts Reveals Key Differences in Genes Associated with Fibrosis Moore, A. L., Marshall, C. D., Litzenburger, U., Barnes, L., Ransom, R., Hu, M., Leavitt, T., Chang, H. Y., Longaker, M. T. ELSEVIER SCIENCE INC. 2017: S200–S201
  • GENOMIC AND EPIGENOMIC ANALYSIS OF ENGRAILED-1 FIBROBLASTS PREDICT FIBROGENIC ROLE IN SCARRING Hu, M. S., Walmsley, G., Leavitt, T., Litzenburger, U., Marshall, C., Sinha, R., Maan, Z., Barnes, L., Duscher, D., Weissman, I., Gurtner, G., Chang, H., Lorenz, H. P., Longaker, M. WILEY. 2017: A16
  • Excess Dermal Tissue Remodeling In Vivo: Does It Settle? Plastic and reconstructive surgery Leavitt, T., Hu, M. S., Zielins, E. R., Barnes, L. A., Marshall, C. D., Wan, D. C., Lorenz, H. P., Gurtner, G. C., Longaker, M. T. 2017; 139 (2): 415e-424e

    Abstract

    Surgical manipulation of skin may result in undesired puckering of excess tissue, which is generally assumed to settle over time. In this article, the authors address the novel question of how this excess tissue remodels.Purse-string sutures (6-0 nylon) were placed at the midline dorsum of 22 wild-type BALB/c mice in a circular pattern marked with tattoo ink. Sutures were cinched and tied under tension in the treatment group, creating an excess tissue deformity, whereas control group sutures were tied without tension. After 2 or 4 weeks, sutures were removed. The area of tattooed skin was measured up to 56 days after suture removal. Histologic analysis was performed on samples harvested 14 days after suture removal.The majority of excess tissue deformities flattened within 2 days after suture removal. However, the sutured skin in the treatment group decreased in area by an average of 18 percent from baseline (n = 9), compared to a 1 percent increase in the control group (n = 10) at 14 days after suture removal (p < 0.05). This was similarly observed at 28 days (treatment, -11.7 percent; control, 4.5 percent; n = 5; p = 0.0243). Despite flattening, deformation with purse-string suture correlated with increased collagen content of skin, in addition to increased numbers of myofibroblasts. Change in area did not correlate with duration of suture placement.Excess dermal tissue deformities demonstrate the ability to remodel with gross flattening of the skin, increased collagen deposition, and incomplete reexpansion to baseline area. Further studies will reveal whether our findings in this mouse model translate to humans.

    View details for DOI 10.1097/PRS.0000000000003026

    View details for PubMedID 28121870

  • Rapid Isolation of BMPR-IB plus Adipose-Derived Stromal Cells for Use in a Calvarial Defect Healing Model JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Marshall, C. D., Zielins, E. R., Brett, E. A., Blackshear, C. P., Hu, M. S., Leavitt, T., Barnes, L. A., Lorenz, H. P., Longaker, M. T., Wan, D. C. 2017

    Abstract

    Invasive cancers, major injuries, and infection can cause bone defects that are too large to be reconstructed with preexisting bone from the patient's own body. The ability to grow bone de novo using a patient's own cells would allow bony defects to be filled with adequate tissue without the morbidity of harvesting native bone. There is interest in the use of adipose-derived stromal cells (ASCs) as a source for tissue engineering because these are obtained from an abundant source: the patient's own adipose tissue. However, ASCs are a heterogeneous population and some subpopulations may be more effective in this application than others. Isolation of the most osteogenic population of ASCs could improve the efficiency and effectiveness of a bone engineering process. In this protocol, ASCs are obtained from subcutaneous fat tissue from a human donor. The subpopulation of ASCs expressing the marker BMPR-IB is isolated using FACS. These cells are then applied to an in vivo calvarial defect healing assay and are found to have improved osteogenic regenerative potential compared with unsorted cells.

    View details for DOI 10.3791/55120

    View details for Web of Science ID 000397847700048

    View details for PubMedID 28287559

  • Rapid Isolation of BMPR-IB plus Adipose-Derived Stromal Cells for Use in a Calvarial Defect Healing Model JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Marshall, C. D., Zielins, E. R., Brett, E. A., Blackshear, C. P., Hu, M. S., Leavitt, T., Barnes, L. A., Lorenz, H. P., Longaker, M. T., Wan, D. C. 2017

    Abstract

    Invasive cancers, major injuries, and infection can cause bone defects that are too large to be reconstructed with preexisting bone from the patient's own body. The ability to grow bone de novo using a patient's own cells would allow bony defects to be filled with adequate tissue without the morbidity of harvesting native bone. There is interest in the use of adipose-derived stromal cells (ASCs) as a source for tissue engineering because these are obtained from an abundant source: the patient's own adipose tissue. However, ASCs are a heterogeneous population and some subpopulations may be more effective in this application than others. Isolation of the most osteogenic population of ASCs could improve the efficiency and effectiveness of a bone engineering process. In this protocol, ASCs are obtained from subcutaneous fat tissue from a human donor. The subpopulation of ASCs expressing the marker BMPR-IB is isolated using FACS. These cells are then applied to an in vivo calvarial defect healing assay and are found to have improved osteogenic regenerative potential compared with unsorted cells.

    View details for DOI 10.3791/55120

    View details for Web of Science ID 000397847700048

    View details for PubMedID 28287559

  • Sanativo Wound Healing Product Does Not Accelerate Reepithelialization in a Mouse Cutaneous Wound Healing Model. Plastic and reconstructive surgery Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Cheung, A. T., Malhotra, S., Lorenz, H. P., Delp, S. L., Quake, S. R., Longaker, M. T. 2017; 139 (2): 343-352

    Abstract

    Sanativo is an over-the-counter Brazilian product derived from Amazon rainforest plant extract that is purported to improve the healing of skin wounds. Two experimental studies have shown accelerated closure of nonsplinted excisional wounds in rat models. However, these models allow for significant contraction of the wound and do not approximate healing in the tight skin of humans.Full-thickness excisional wounds were created on the dorsal skin of mice and were splinted with silicone rings, a model that forces the wound to heal by granulation and reepithelialization. Sanativo or a control solution was applied either daily or every other day to the wounds. Photographs were taken every other day, and the degree of reepithelialization of the wounds was determined.With both daily and every-other-day applications, Sanativo delayed reepithelialization of the wounds. Average time to complete healing was faster with control solution versus Sanativo in the daily application group (9.4 versus 15.2 days; p < 0.0001) and the every-other-day application group (11 versus 13 days; p = 0.017). The size of visible scar at the last time point of the study was not significantly different between the groups, and no differences were found on histologic examination.Sanativo wound healing compound delayed wound reepithelialization in a mouse splinted excisional wound model that approximates human wound healing. The size of visible scar after complete healing was not improved with the application of Sanativo. These results should cast doubt on claims that this product can improve wound healing in humans.

    View details for DOI 10.1097/PRS.0000000000003013

    View details for PubMedID 28121865

  • Minimizing Skin Scarring through Biomaterial Design. Journal of functional biomaterials Moore, A. L., Marshall, C. D., Longaker, M. T. 2017; 8 (1)

    Abstract

    Wound healing continues to be a major burden to patients, though research in the field has expanded significantly. Due to an aging population and increasing comorbid conditions, the cost of chronic wounds is expected to increase for patients and the U.S. healthcare system alike. With this knowledge, the number of engineered products to facilitate wound healing has also increased dramatically, with some already in clinical use. In this review, the major biomaterials used to facilitate skin wound healing will be examined, with particular attention allocated to the science behind their development. Experimental therapies will also be evaluated.

    View details for DOI 10.3390/jfb8010003

    View details for PubMedID 28117733

  • Delivery of monocyte lineage cells in a biomimetic scaffold enhances tissue repair. JCI insight Hu, M. S., Walmsley, G. G., Barnes, L. A., Weiskopf, K., Rennert, R. C., Duscher, D., Januszyk, M., Maan, Z. N., Hong, W. X., Cheung, A. T., Leavitt, T., Marshall, C. D., Ransom, R. C., Malhotra, S., Moore, A. L., Rajadas, J., Lorenz, H. P., Weissman, I. L., Gurtner, G. C., Longaker, M. T. 2017; 2 (19)

    Abstract

    The monocyte lineage is essential to normal wound healing. Macrophage inhibition or knockout in mice results in impaired wound healing through reduced neovascularization, granulation tissue formation, and reepithelialization. Numerous studies have either depleted macrophages or reduced their activity in the context of wound healing. Here, we demonstrate that by increasing the number of macrophages or monocytes in the wound site above physiologic levels via pullulan-collagen composite dermal hydrogel scaffold delivery, the rate of wound healing can be significantly accelerated in both wild-type and diabetic mice, with no adverse effect on the quality of repair. Macrophages transplanted onto wounds differentiate into M1 and M2 phenotypes of different proportions at various time points, ultimately increasing angiogenesis. Given that monocytes can be readily isolated from peripheral blood without in vitro manipulation, these findings hold promise for translational medicine aimed at accelerating wound healing across a broad spectrum of diseases.

    View details for PubMedID 28978794

  • Intestinal Smooth Muscle Cell Migration May Contribute to Abdominal Adhesion Formation Marshall, C. D., Hu, M. S., Leavitt, T., Ransom, R. C., Barnes, L. A., Lorenz, H., Longaker, M. T. ELSEVIER SCIENCE INC. 2016: E106–E107
  • Engrailed-1 Identifies the Fibroblast Lineage Responsible for the Transition from Fetal Scarless to Adult Scarring Cutaneous Wound Repair Hu, M. S., Walmsley, G. G., Maan, Z. N., Sinha, R., Leavitt, T., Marshall, C. D., Weissman, I. L., Gurtner, G. C., Longaker, M. T., Lorenz, H. ELSEVIER SCIENCE INC. 2016: S96–S97
  • Scarless wound healing: finding the right cells and signals. Cell and tissue research Leavitt, T., Hu, M. S., Marshall, C. D., Barnes, L. A., Lorenz, H. P., Longaker, M. T. 2016; 365 (3): 483-493

    Abstract

    From the moment we are born, every injury to the skin has the potential to form a scar, many of which can impair form and/or function. As such, scar management constitutes a billion-dollar industry. However, effectively promoting scarless wound healing remains an elusive goal. The complex interactions of wound healing contribute to our inability to recapitulate scarless wound repair as it occurs in nature, such as in fetal skin and the oral mucosa. However, many new advances have occurred in recent years, some of which have translated scientific findings from bench to bedside. In vivo lineage tracing has helped establish a variety of novel cellular culprits that may act as key drivers of the fibrotic response. These newly characterized cell populations present further targets for therapeutic intervention, some of which have previously demonstrated promising results in animal models. Here, we discuss several recent studies that identify exciting approaches for diminishing scar formation. Particular attention will also be paid to the canonical Wnt/β-catenin signaling pathway, which plays an important role in both embryogenesis and tissue repair. New insights into the differential effects of Wnt signaling on heterogeneous fibroblast and keratinocyte populations within the skin further demonstrate methods by which wound healing can be re-directed to a more fetal scarless phenotype. Graphical abstract Recent approaches to reducing scar formation. Representation showing novel scientific approaches for decreasing scar formation, including the targeting of pro-fibrotic cell populations based on surface molecule expression (e.g. DPP4(+) fibroblasts, ADAM12(+) pericytes). Modulation of cellular mechanotransduction pathways are another means to reduce scar formation, both at the molecular level or, macroscopically with dressings designed to offload tension, at cutaneous wound sites (ADAM12 a disintegrin and metalloprotease 12, DPP4 dipeptidyl peptidase-4, FAK focal adhesion kinase).

    View details for DOI 10.1007/s00441-016-2424-8

    View details for PubMedID 27256396

    View details for PubMedCentralID PMC5010960

  • SANATIVO WORSENS MURINE SKIN WOUND HEALING Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Longaker, M. T. WILEY-BLACKWELL. 2016: A17
  • WOUNDS OUTCOMPETE TUMORS FOR NEOVASCULARIZATION Hu, M. S., Maan, Z. N., Hong, W., Leavitt, T., Marshall, C. D., Rennert, R. C., Walmsley, G. G., Gurtner, G. C., Giaccia, A. J., Lorenz, H. P., Longaker, M. T. WILEY-BLACKWELL. 2016: A12
  • IN VIVO REMODELING OF EXCESS TISSUE DEFORMITIES FOLLOWING PROLONGED MECHANICAL DEFORMATION Leavitt, T., Hu, M. S., Barnes, L. A., Zielins, E. R., Marshall, C. D., Wan, D. C., Gurtner, G. C., Lorenz, H., Longaker, M. T. WILEY-BLACKWELL. 2016: A15
  • Mesenchymal Stromal Cells as Cell-Based Therapeutics for Wound Healing STEM CELLS INTERNATIONAL Malhotra, S., Hu, M. S., Marshall, C. D., Leavitt, T., Cheung, A. T., Gonzalez, J. G., Kaur, H., Lorenz, H. P., Longaker, M. T. 2016

    Abstract

    Chronic wounds are a source of substantial morbidity for patients and are a major financial burden for the healthcare system. There are no current therapies that reliably improve nonhealing wounds or reverse pathological scarring. Mesenchymal stromal cells (MSCs) are a promising source of novel cell-based therapies due to the ease of their harvest and their integral role in the native wound repair process. Recent work has addressed the problems of loss of plasticity and off-target delivery through use of modern bioengineering techniques. Here we describe the applications of MSCs harvested from different sources to the wound healing process and recent advances in delivery of MSCs to targeted sites of injury.

    View details for DOI 10.1155/2016/4157934

    View details for Web of Science ID 000373501200001

    View details for PubMedID 26966438

    View details for PubMedCentralID PMC4757746

  • Stem cells and chronic wound healing: state of the art CHRONIC WOUND CARE MANAGEMENT AND RESEARCH Leavitt, T., Hu, M. S., Marshall, C. D., Barnes, L. A., Longaker, M. T., Lorenz, H. 2016; 3: 7–27
  • Plug the Hole-A Bailout Option for Acute Focal Aortic Rupture. Annals of vascular surgery Zayed, M. A., Marshall, C., Dake, M., Lee, J. T. 2016; 30: 309 e5-9

    Abstract

    Focal aortic rupture may result from expanding aneurysms, penetrating aortic wall ulcerations, or virulent infections. An urgent repair of paravisceral focal aortic rupture is associated with high morbidity. A staged repair approach may provide an alternative option.A 64-year-old woman presented with acute focal rupture of the posterior paravisceral aortic wall and was progressing to hemorrhagic shock and mesenteric ischemia. Given the patient's dire condition, an endovascular approach was used to plug her focal aortic wall defect using a ventricular septal defect occluder device. Subsequently, the patient underwent resuscitation, stabilization, and operative exploration. Postoperatively, she recovered well from this staged approach.This case provides an example of a staged endovascular plugging of an acute paravisceral focal aortic rupture. In select cases, this type of repair strategy is feasible, until off-the-shelf endovascular repair options become a reality.

    View details for DOI 10.1016/j.avsg.2015.07.033

    View details for PubMedID 26522581

  • Repair of Anomalous Left Coronary Artery From the Right Pulmonary Artery: A Series of Nine Cases. World journal for pediatric & congenital heart surgery Marshall, C. D., Weigand, J., Sambatakos, P., Hayes, D. A., Chen, J. M., Quaegebeur, J. M., Bacha, E., Richmond, M. E. 2015; 6 (3): 382-386

    Abstract

    Repair of anomalous left coronary artery from the right pulmonary artery presents a particular technical challenge to the congenital cardiac surgeon. There is disagreement in the literature over the optimal technique for this defect, with some authors advocating for unroofing of the periaortic segment of coronary artery, while others prefer direct aortic reimplantation of the artery.We performed a retrospective study examining outcomes of patients who were repaired for this anomaly at our institution. In-hospital and outpatient follow-up data were analyzed.Nine patients were identified. Most patients had poor left ventricular function at the time of surgery. All patients in our series were repaired using the direct coronary transfer technique. To date there were no mortalities among the study participants. At last follow-up, all patients with available echocardiograms had normal ventricular function. One patient required reoperation for anastomotic stenosis.We demonstrate that using the technique of direct coronary transfer to the aorta, we have achieved excellent results with repair of this defect.

    View details for DOI 10.1177/2150135115579918

    View details for PubMedID 26180152

  • Repair of Anomalous Left Coronary Artery From the Pulmonary Artery in the Modern Era: Preoperative Predictors of Immediate Postoperative Outcomes and Long Term Cardiac Follow-up PEDIATRIC CARDIOLOGY Weigand, J., Marshall, C. D., Bacha, E. A., Chen, J. M., Richmond, M. E. 2015; 36 (3): 489-497

    Abstract

    Little is known about preoperative factors affecting postoperative morbidity following anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) repair. This study aimed at identifying predictors of postoperative outcomes, including mortality and left ventricle (LV) normalization. A retrospective, single institution review was conducted on forty-four ALCAPA repairs from April 1991 to November 2012. Preoperative clinical data and echocardiograms were analyzed. Postoperative outcomes included duration of intensive care supports and mortality. Time to normalization of LV end diastolic dimension (LVEDD) and function were assessed. Logistic regression and Cox proportional hazard analyses were used to correlate preoperative variables to postoperative outcomes. Forty-four patients underwent ALCAPA repair. No in-hospital or late mortality was observed. LVEDD, weight, and LV shortening fraction (SF) independently predicted duration of postoperative inotropic support. LVEDD and body surface area independently predicted the duration of postoperative intubation. For the infant majority, younger age predicted longer duration of postoperative intubation (p = 0.048) and LVEDD Z-score independently predicted duration of postoperative IV inotropic support (p = 0.042). LV function normalized in all patients for whom follow-up data was available. LVEDD Z-score independently predicted time to normalization of LV function (p = 0.013). ALCAPA repair in the current era has excellent outcomes, with no mortality in our cohort. Immediate postoperative morbidities are influenced by patient size, LVEDD, and preoperative SF. Outcomes of infantile ALCAPA are influenced by the degree of LV dilation. Time to normalization of LV function is related to LVEDD. Limitations included retrospective evaluation of LV function.

    View details for DOI 10.1007/s00246-014-1038-8

    View details for Web of Science ID 000350034000005

    View details for PubMedID 25301273

  • Repair of Anomalous Left Coronary Artery From the Right Pulmonary Artery: A Series of Nine Cases World J Pediatr Congenit Heart Surg Marshall, C. D., Weigand, J., Sambatakos, P., Hayes, D., Chen, J., Quaegebeur, J., Bacha, E., Richmond, M. 2015; 6 (3): 382-386

    View details for DOI 10.1177/2150135115579918

  • A Comparison of Traditional versus Contemporary Immunosuppressive Regimens in Pediatric Heart Recipients JOURNAL OF PEDIATRICS Marshall, C. D., Richmond, M. E., Singh, R. K., Gilmore, L., Beddows, K., Chen, J. M., Addonizio, L. J. 2013; 163 (1): 132-136

    Abstract

    To assess the differences in rejection and infection complications between the most common contemporary immunosuppression regimen in pediatric heart transplantation (cytolytic induction, tacrolimus based) and classic triple-therapy (cyclosporine based without induction).We performed a retrospective, historical-control, observational study comparing outcomes in patients who underwent traditional immunosuppression (control group, n = 64) with those for whom the contemporary protocol was used (n = 39). Episodes of rejection, viremia (cytomegalovirus or Epstein-Barr virus), serious bacterial or fungal infections, anemia or neutropenia requiring treatment in the first year after heart transplantation, and 1-year survival were compared between traditional and contemporary immunosuppression groups.The 2 groups were similar with respect to baseline demographics. There were no differences in risk of cytomegalovirus, Epstein-Barr virus, or bacterial or fungal infections in the first year post-transplantation. Patients in the contemporary group were more likely to need therapy for anemia (51% vs 14%, P < .001) or neutropenia (10% vs 0%, P = .019). However, more contemporary protocol patients were rejection-free in the first year post-transplantation (63% vs 41%, P = .03). Overall graft survival was similar between groups (P = .15).A contemporary immunosuppression regimen using tacrolimus, mycophenolate mofetil, and induction was associated with less rejection in the first year, with no difference in the risk of infection but greater risk of anemia and neutropenia requiring treatment. Long-term follow-up on these patients will evaluate the impact of the immunosuppression regimen on survival.

    View details for DOI 10.1016/j.jpeds.2012.12.075

    View details for Web of Science ID 000321494000028

    View details for PubMedID 23391044

  • Detection of Hypoventilation by Capnography and Its Association With Hypoxia in Children Undergoing Sedation With Ketamine PEDIATRIC EMERGENCY CARE Langhan, M. L., Chen, L., Marshall, C., Santucci, K. A. 2011; 27 (5): 394-397

    Abstract

    Hypopneic hypoventilation, a decrease in tidal volume without a change in respiratory rate, is not easily detected by standard monitoring practices during sedation but can be detected by capnography. Our goal was to determine the frequency of hypopneic hypoventilation and its association with hypoxia in children undergoing sedation with ketamine.Children who received intravenous ketamine with or without midazolam for sedation in a pediatric emergency department were prospectively enrolled. Heart rate, respiratory rate, pulse oximetry, and end-tidal carbon dioxide (ET(CO2)) levels were recorded every 30 seconds.Fifty-eight subjects were included in this study. Fifty percent of subjects had recorded ET(CO2) values less than 30 mm Hg without a rise in respiratory rate. Twenty-eight percent of subjects experienced a decrease in pulse oximetry less than 95%. Patients who experienced a persistent decrease in ET(CO2) at least 30 seconds in length were much more likely to have a persistent decrease in pulse oximetry than those with normal or transient decreases in ET(CO2) (relative risk, 6.6; 95% confidence interval, 1.4-30.5). Decreases in ET(CO2) occurred on an average of 3.7 minutes before decreases in pulse oximetry.Hypopneic hypoventilation as detected by capnography is common in children undergoing sedation with ketamine with or without midazolam. Hypoxia is frequently preceded by low ET(CO2) levels. Further studies are needed to determine if the addition of routine monitoring with capnography can reduce the frequency of hypoxia in children undergoing sedation.

    View details for DOI 10.1097/PEC.0b013e318217b538

    View details for Web of Science ID 000290297200009

    View details for PubMedID 21494162

  • Benefits & Complications of Induction Therapy in a Single-Center Cohort of Pediatric Heart Recipients. Richmond, M. E., Marshall, C., Singh, R. K., Gilmore, L. A., Beddows, K., Chen, J. M., Addonizio, L. J. WILEY-BLACKWELL. 2011: 235–36
  • Relationship of Serum S100B Levels and Intracranial Injury in Children With Closed Head Trauma PEDIATRICS Bechtel, K., Frasure, S., Marshall, C., Dziura, J., Simpson, C. 2009; 124 (4): E697-E704

    Abstract

    To determine if serum levels of S100B are higher in children with CHT and ICI as detected by cranial CT and if long bone fractures affect the level of S100B in children with CHT and skeletal injury.Children <18 years of age who presented to an urban pediatric emergency department or were transferred from a referral hospital within 6 hours after accidental closed head trauma and who underwent cranial computed tomography were enrolled prospectively. Mean serum S100B levels for children with or without intracranial injury (ICI) and long-bone fractures were evaluated through analysis of covariance.One hundred fifty-two children, 24 with ICI and 128 without ICI, were enrolled prospectively. Twenty-five children had long-bone fractures. Children with ICI were significantly younger than those without ICI (6.9 vs 9.8 years; P = .01). The time of venipuncture after injury was significantly later in children with ICI (P = .03). Mean S100B levels were significantly greater for children with ICI (212.9 vs 84.4 ng/L; P = .001), children with long-bone fractures (P = .008), and nonwhite children (P = .03). After controlling for time of venipuncture, long-bone fractures, and race, mean S100B levels were still greater for children with ICI (409 vs 118 ng/L; P = .001). The ability of serum S100B measurements to detect ICI, determined as the area under the curve, was 0.67.After controlling for time of venipuncture, long-bone fractures, and race, S100B levels were still higher in children with ICI than in those without ICI. However, the ability of serum S100B measurements to detect ICI was poor.

    View details for DOI 10.1542/peds.2008-1493

    View details for Web of Science ID 000270274300052

    View details for PubMedID 19786430