All Publications

  • Acellular Dermal Matrix Reduces Myofibroblast Presence in the Breast Capsule. Plastic and reconstructive surgery. Global open Tevlin, R., Borrelli, M. R., Irizarry, D., Nguyen, D., Wan, D. C., Momeni, A. 2019; 7 (5): e2213


    Background: Capsular contracture remains a common complication after implant-based breast reconstruction. Previous work has suggested that the use of acellular dermal matrix (ADM) reduces the rate of capsular contracture, though little is understood about the underlying mechanism. As myofibroblasts are believed to be the key cells implicated in contracture formation, we hypothesized that ADM would result in a reduction in periprosthetic myofibroblast concentration.Methods: Five patients who underwent immediate prepectoral tissue expander placement with anterior ADM coverage and an inferior cuff were included. At the second stage, tissue samples were obtained of both ADM and capsule from each reconstructed breast. Samples were then prepared for hematoxylin and eosin staining and immunohistochemistry for myofibroblast identification (alpha smooth muscle actin and vimentin positive and desmin negative) and analysis. Experimental values are presented as mean ± SD unless otherwise stated. Statistical significance was determined using unpaired t test.Results: Successful incorporation of ADM was noted in all cases. A significant reduction in myofibroblast concentration was noted in the ADM versus the capsule (P = 0.0018). This was paralleled by significantly thicker periprosthetic capsule formation overlying the formerly raw pectoralis major muscle, that is, not covered by ADM (P < 0.0001).Conclusions: In the presence of ADM, there are significantly fewer myofibroblasts in breast capsules and thinner capsules on histology. Given the central role of myofibroblasts in the development of clinically significant capsular contracture, this study unmasks a possible mechanism for the protective effect of ADM with respect to capsular contracture development.

    View details for DOI 10.1097/GOX.0000000000002213

    View details for PubMedID 31333946

  • Fat Grafting into Younger Recipients Improves Volume Retention in an Animal Model PLASTIC AND RECONSTRUCTIVE SURGERY Chung, N. N., Ransom, R. C., Blackshear, C. P., Irizarry, D. M., Yen, D., Momeni, A., Lee, G. K., Nguyen, D. H., Longaker, M. T., Wan, D. C. 2019; 143 (4): 1067–75
  • Fat Grafting into Younger Recipients Improves Volume Retention in an Animal Model. Plastic and reconstructive surgery Chung, N. N., Ransom, R. C., Blackshear, C. P., Irizarry, D. M., Yen, D., Momeni, A., Lee, G. K., Nguyen, D. H., Longaker, M. T., Wan, D. C. 2019


    BACKGROUND: Soft tissue deficits associated with various craniofacial anomalies can be addressed by fat grafting, although outcomes remain unpredictable. Furthermore, consensus does not exist for timing of these procedures. While some advocate approaching soft tissue reconstruction after the underlying skeletal foundation has been corrected, other studies have suggested earlier grafting may exploit a younger recipient niche that is more conducive for fat graft survival. As there is a dearth of research investigating effects of recipient age on fat graft volume retention, this study compared the effectiveness of fat grafting in younger versus older animals through a longitudinal, in vivo analysis.METHODS: Human lipoaspirate from three healthy female donors was grafted subcutaneously over the calvarium of immunocompromised mice. Volume retention over 8 weeks was evaluated using micro-computed tomography in three experimental ages - 3-weeks old, 6-months old, and 1-year old. Histology was performed on explanted grafts to evaluate graft health and vascularity. Recipient site vascularity was also evaluated by confocal microscopy.RESULTS: Greatest retention of fat graft volume was noted in the youngest group compared to both older groups (*p < 0.05) at 6 and 8 weeks following grafting. Histological and immunohistochemical analyses revealed that improved retention in younger groups was associated with greater fat graft integrity and more robust vascularization.CONCLUSION: Our study provides evidence that grafting fat into a younger recipient site correlates with improved volume retention over time, suggesting that beginning soft tissue reconstruction with fat grafting in patients at an earlier age may be preferable to late correction.

    View details for PubMedID 30730498

  • 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


    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

  • Reduced Scar Thickness Achieved by Topical Doxycycline Is Mediated by Specific Skin Fibroblast Populations and Not Immune Cell Infiltrate Moore, A. L., Murphy, M. P., Irizarry, D. M., Des Jardins-Park, H. E., Duoto, B. A., Mascharak, S., Foster, D. S., Jones, R., Wernig, G., Longaker, M. T. ELSEVIER SCIENCE INC. 2018: S210–S211
  • Utilizing Confocal Microscopy to Characterize Human and Mouse Adipose Tissue. Tissue engineering. Part C, Methods Blackshear, C., Borrelli, M. R., Shen, E. Z., Ransom, R. C., Chung, N. N., Vistnes, S., Irizarry, D., Nazerali, R., Momeni, A., Longaker, M. T., Wan, D. C. 2018


    Significant advances in our understanding of human obesity, endocrinology, and metabolism have been made possible by murine comparative models, in which anatomically analogous fat depots are utilized; however, current research has questioned how truly analogous these depots are. In this study, we assess the validity of the analogy from the perspective of cellular architecture. Whole tissue mounting, confocal microscopy, and image reconstruction software were employed to characterize the three-dimensional structure of the inguinal fat pad in mice, gluteofemoral fat in humans, and subcutaneous adipose tissue of the human abdominal wall. Abdominal and gluteofemoral adipose tissue specimens from 12 human patients and bilateral inguinal fat pads from 12 mice were stained for adipocytes, blood vessels, and a putative marker for adipose-derived multipotent progenitor cells, CD34. Samples were whole-mounted and imaged with laser scanning confocal microscopy. Expectedly, human adipocytes were larger and demonstrated greater size heterogeneity. Mouse fat displayed significantly higher vascular density compared to human fat when normalized to adipocyte count. There was no significant difference in the concentration of CD34+ stromal cells from either species. However, the mean distance between CD34+ stromal cells and blood vessels was significantly greater in human fat. Finally, mouse inguinal fat contained larger numbers of brown adipocytes than did human gluteofemoral or human abdominal fat. Overall, the basic architecture of human adipose tissue differs significantly from that of mice. Insofar as human gluteofemoral fat differs from human abdominal adipose tissue, it was closer to mouse inguinal fat, being its comparative developmental analogue. These differences likely confer variance in functional properties between the two sources, and thus must be considered when designing murine models of human disease.

    View details for PubMedID 30215305

  • Three-Dimensional Ultrasound Versus Computerized Tomography in Fat Graft Volumetric Analysis ANNALS OF PLASTIC SURGERY Blackshear, C., Rector, M., Chung, N., Irizarry, D., Flacco, J., Brett, E., Momeni, A., Lee, G., Longaker, M. T., Wan, D. C. 2018; 80 (3): 293–96


    Studies evaluating fat grafting in mice have frequently used micro-computed tomography (micro-CT) as an accurate radiographic tool to measure longitudinal volume retention without killing the animal. Over the past decade, however, microultrasonography has emerged as an equally powerful preclinical imaging tool. Given their respective strengths in 3-dimensional reconstruction, there is no study to our knowledge that directly compares micro-CT with microultrasound in volumetric analysis. In this study, we compared the performance of micro-CT with microultrasound in the evaluation of adipose tissue graft volume in a murine model. Fifteen immunodeficient mice were given 200 μL of adipose tissue grafts. In vivo volumetric analysis of the grafts by micro-CT and microultrasound was conducted at discrete time points up to postoperative day 105. Three mice were killed at multiple time points, and explanted grafts were reimaged by CT and ultrasound, as mentioned previously. Analysis revealed that in vivo graft volumes measured by micro-CT do not differ significantly from those of microultrasound. Furthermore, both micro-CT and microultrasound were capable of accurately measuring fat grafts as in vivo volumes closely correlated with explanted volumes. Finally, ultrasound was found to yield improved soft tissue contrast compared with micro-CT. Therefore, either modality may be used, depending on experimental needs.

    View details for DOI 10.1097/SAP.0000000000001183

    View details for Web of Science ID 000425352000021

    View details for PubMedID 28678028

    View details for PubMedCentralID PMC5752634

  • Deferoxamine Preconditioning of Irradiated Tissue Improves Perfusion and Fat Graft Retention PLASTIC AND RECONSTRUCTIVE SURGERY Flacco, J., Chung, N., Blackshear, C. P., Irizarry, D., Momeni, A., Lee, G. K., Dung Nguyen, Gurtner, G. C., Longaker, M. T., Wan, D. C. 2018; 141 (3): 655–65


    Radiation therapy is a mainstay in the treatment of many malignancies, but collateral damage to surrounding tissue, with resultant hypovascularity, fibrosis, and atrophy, can be difficult to reconstruct. Fat grafting has been shown to improve the quality of irradiated skin, but volume retention of the graft is significantly decreased. Deferoxamine is a U.S. Food and Drug Administration-approved iron-chelating medication for acute iron intoxication and chronic iron overload that has also been shown to increase angiogenesis. The present study evaluates the effects of deferoxamine treatment on irradiated skin and subsequent fat graft volume retention.Mice underwent irradiation to the scalp followed by treatment with deferoxamine or saline and perfusion and were analyzed using laser Doppler analysis. Human fat grafts were then placed beneath the scalp and retention was also followed up to 8 weeks radiographically. Finally, histologic evaluation of overlying skin was performed to evaluate the effects of deferoxamine preconditioning.Treatment with deferoxamine resulted in significantly increased perfusion, as demonstrated by laser Doppler analysis and CD31 immunofluorescent staining (p < 0.05). Increased dermal thickness and collagen content secondary to irradiation, however, were not affected by deferoxamine (p > 0.05). Importantly, fat graft volume retention was significantly increased when the irradiated recipient site was preconditioned with deferoxamine (p < 0.05).The authors' results demonstrated increased perfusion with deferoxamine treatment, which was also associated with improved fat graft volume retention. Preconditioning with deferoxamine may thus enhance fat graft outcomes for soft-tissue reconstruction following radiation therapy.

    View details for PubMedID 29135894

    View details for PubMedCentralID PMC5826842

  • An Improved Humanized Mouse Model for Excisional Wound Healing Using Double Transgenic Mice ADVANCES IN WOUND CARE Hu, M. S., Cheng, J., Borrelli, M. R., Leavitt, T., Walmsley, G. G., Zielins, E. R., Hong, W., Cheung, A. M., Duscher, D., Maan, Z. N., Irizarry, D. M., Stephan, B., Parsa, F., Wan, D. C., Gurtner, G. C., Lorenz, H., Longaker, M. T. 2018; 7 (1): 11–17


    Objective: Splinting full-thickness cutaneous wounds in mice has allowed for a humanized model of wound healing. Delineating the epithelial edge and assessing time to closure of these healing wounds via macroscopic visualization have remained a challenge. Approach: Double transgenic mice were created by crossbreeding K14-Cre and ROSAmT/mG reporter mice. Full-thickness excisional wounds were created in K14-Cre/ROSAmT/mG mice (n = 5) and imaged using both normal and fluorescent light on the day of surgery, and every other postoperative day (POD) until wound healing was complete. Ten blinded observers analyzed a series of images from a single representative healing wound, taken using normal or fluorescent light, to decide the POD when healing was complete. K14-Cre/ROSAmT/mG mice (n = 4) were subsequently sacrificed at the four potential days of rated wound closure to accurately determine the histological point of wound closure using microscopic fluorescence imaging. Results: Average time to wound closure was rated significantly longer in the wound series images taken using normal light, compared with fluorescent light (mean POD 13.6 vs. 11.6, *p = 0.008). Fluorescence imaging of histological samples indicated that reepithelialization was complete at 12 days postwounding. Innovation: We describe a novel technique, using double transgenic mice K14-Cre/ROSAmT/mG and fluorescence imaging, to more accurately determine the healing time of wounds in mice upon macroscopic evaluation. Conclusion: The accuracy by which wound healing can be macroscopically determined in vivo in mouse models of wound healing is significantly enhanced using K14-Cre/ROSAmT/mG double transgenic mice and fluorescence imaging.

    View details for PubMedID 29344430

  • Cell-Based Soft Tissue Reconstruction in a Hydrogel Scaffold ANNALS OF PLASTIC SURGERY Blackshear, C. P., Flacco, J. S., Vistnes, S. M., Chung, N. N., Irizarry, D., Brett, E. A., Yen, D. J., Momeni, A., Longaker, M. T., Wan, D. C. 2017; 79 (6): 618–22


    Renevia is a hyaluronin-gelatin crosslinked matrix scaffold that has been studied as an alternative to adipose transfer in soft tissue reconstruction. It is designed to emulate the native extracellular matrix environment by supporting stromal vascular fraction (SVF) cell attachment, survival, and proliferation, thus promoting cell-based volume restoration. However, the concentration of incorporated cells for a clinically relevant result has yet to be determined.Five experimental groups of seven CD-1 nude immunodeficient mice were given 250 μL grafts of the following composition: 1 million human SVF cells per mL of Renevia scaffold, 6 million human SVF cells per mL scaffold, 12 million human SVF cells per mL scaffold, Renevia scaffold-alone or human adipose tissue-alone. Volumetric analysis was conducted at discrete time points over 16 weeks using 3-dimensional ultrasound, after which time the grafts were explanted for histologic analysis.At the conclusion of the study at week 16, the Renevia scaffold group incorporating the highest concentration of human SVF cells (12 million cells per mL scaffold) had significantly greater volume retention compared with the 2 lower concentrations, scaffold-alone and fat-alone groups. Histology of the 12 million scaffold group revealed abundant adipocyte formation within the scaffold, exceeding that observed in the 6 million, 1 million, and scaffold-alone groups. The 12 million group also demonstrated significantly increased vascularity per CD31 staining.Stromal vascular fraction cells coupled with Renevia hydrogel scaffold can enhance soft tissue volume reconstruction. In this study, we observed the greatest effect with 12 million cells per mL. From the perspective of volume retention, incorporation of higher concentrations of SVF cells with Renevia may be an alternative to conventional adipose tissue grafting.

    View details for PubMedID 28671889

    View details for PubMedCentralID PMC5677558

  • Characterization of Adipose Tissue Using 3-Dimensional Confocal Microscopy Blackshear, C. P., Irizarry, D. M., Montenegro, C. F., Wan, D. C. ELSEVIER SCIENCE INC. 2017: S161
  • Doxycyline Improves Wound Healing via Nonantibiotic Associated Mechanisms Moore, A. L., Murphy, M. P., Irizarry, D. M., Brett, E. A., Wernig, G., Longaker, M. T. ELSEVIER SCIENCE INC. 2017: S162–S163
  • Fat Graft Retention Decreases with Recipient Age Montenegro, C. F., Flacco, J., Chung, N. N., Irizarry, D. M., Brett, E. A., Blackshear, C. P., Nguyen, D., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2017: E144–E145
  • Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects PLASTIC AND RECONSTRUCTIVE SURGERY Irizarry, D. M., Wan, D. C. 2017; 139 (4): 908–9

    View details for PubMedID 28350670

  • The Role of Skeletal Stem Cells in the Reconstruction of Bone Defects. The Journal of craniofacial surgery Murphy, M. P., Irizarry, D., Lopez, M., Moore, A. L., Ransom, R. C., Longaker, M. T., Wan, D. C., Chan, C. K. 2017; 28 (5): 1136–41


    Craniofacial surgery, since its inauguration, has been the culmination of collaborative efforts to solve complex congenital, dysplastic, oncological, and traumatic cranial bone defects. Now, 50 years on from the first craniofacial meeting, the collaborative efforts between surgeons, scientists, and bioengineers are further advancing craniofacial surgery with new discoveries in tissue regeneration. Recent advances in regenerative medicine and stem cell biology have transformed the authors' understanding of bone healing, the role of stem cells governing bone healing, and the effects of the niche environment and extracellular matrix on stem cell fate. This review aims at summarizing the advances within each of these fields.

    View details for PubMedID 28665863

  • Commentary on: Adipose Stem Cell Function Maintained with Age: An Intra-Subject Study of Long-Term Cryopreserved Cells. Aesthetic surgery journal Irizarry, D., Longaker, M. T., Wan, D. C. 2016

    View details for DOI 10.1093/asj/sjw224

    View details for PubMedID 28039122

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