Publications by authors named "Rica Tanaka"

52 Publications

Reply: Quality and Quantity-Cultured Human Mononuclear Cells Improve the Human Fat Graft Vascularization and Survival in an In Vivo Murine Experimental Model.

Plast Reconstr Surg 2021 Aug 30. Epub 2021 Aug 30.

Departments of Plastic and Reconstructive Surgery and Regenerative Therapy Juntendo University School of Medicine Tokyo, Japan.

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http://dx.doi.org/10.1097/PRS.0000000000008348DOI Listing
August 2021

Hard-to-heal wound treatment medical devices: clinical trial protocol in Japan.

J Wound Care 2021 Aug;30(8):666-676

Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

In consultation with academia and the Pharmaceuticals and Medical Devices Agency (PMDA), we have developed guidance for drafting protocols for clinical trials concerning medical devices for the healing of hard-to-heal wounds without ischaemia. The guidance summarises the validity of single-arm trials for hard-to-heal wounds, the definition of hard-to-heal wounds without ischaemia, methods of patient enrolment and clinical endpoints. This review focuses on the logical thinking process that was used when establishing the guidance for improving the efficiency of clinical trials concerning medical devices for hard-to-heal wounds. We particularly focused on the feasibility of conducting single-arm trials and also tried to clarify the definition of hard-to-heal wounds. If the feasibility of randomised control trials is low, conducting single-arm trials should be considered for the benefit of patients. In addition, hard-to-heal wounds were defined as meeting the following two conditions: wounds with a wound area reduction <50% at four weeks despite appropriate standards of care; and wounds which cannot be closed by a relatively simple procedure (for example, suture, skin graft and small flaps). Medical devices for hard-to-heal wound healing are classified into two types: (1) devices for promoting re-epithelialisation; and (2) devices for improving the wound bed. For medical devices for promoting re-epithelialisation, we suggest setting complete wound closure, percent wound area reduction or distance moved by the wound edge as the primary endpoint in single-arm trials for hard-to-heal wounds. For medical devices for improving the wound bed, we suggest setting the period in which wounds can be closed by secondary intention or a simple procedure, such as the primary endpoint.
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http://dx.doi.org/10.12968/jowc.2021.30.8.666DOI Listing
August 2021

Use of Sponge-Foam Inserts in Compression Bandaging of Non-Healing Venous Leg Ulcers.

Ann Vasc Dis 2021 Mar;14(1):46-51

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Sapporo, Hokkaido, Japan.

Venous leg ulcers (VLUs) caused by chronic venous insufficiency are difficult to treat. Outcomes after compression therapy and the current standard of care often used in conjunction with other options vary widely. We examined the effects of foam inserts on sub-bandage pressures in patients with VLUs and compared use of foam inserts in elastic and inelastic compression bandaging. Six patients (≥20 years old) with VLUs and skin perfusion pressure >40 mmHg were included. Each patient underwent weekly treatment regimens of debridement, dressing changes, and dual sponge-insert application followed by elastic (n=3) or inelastic (n=3) compression bandaging. The median resting sub-bandage pressures of the ulcer beds, wound sizes, and healing percentages were recorded. Wound beds were biopsied before and after treatment for histological assessment. Nine healthy volunteers served as controls during preliminary testing. With proper sub-bandage pressures (>35 mmHg), the average healing time was 88.0±66 days, which was shorter than anticipated (i.e., ≥6 months). Combining large and local sponge-foam inserts increased sub-bandage pressures regardless of the compression bandage selected, with marked improvements seen in deeper wounds. Layering one or two sponge-foam inserts beneath compression bandages facilitates uniform and optimal wound-bed pressure, which accelerates the healing of VLUs.
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http://dx.doi.org/10.3400/avd.oa.20-00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991709PMC
March 2021

Ex vivo conditioning of peripheral blood mononuclear cells of diabetic patients promotes vasculogenic wound healing.

Stem Cells Transl Med 2021 Jun 18;10(6):895-909. Epub 2021 Feb 18.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

The quality and quantity of endothelial progenitor cells (EPCs) are impaired in patients with diabetes mellitus patients, leading to reduced tissue repair during autologous EPC therapy. This study aimed to address the limitations of the previously described serum-free Quantity and Quality Control Culture System (QQc) using CD34+ cells by investigating the therapeutic potential of a novel mononuclear cell (MNC)-QQ. MNCs were isolated from 50 mL of peripheral blood of patients with diabetes mellitus and healthy volunteers (n = 13 each) and subjected to QQc for 7 days in serum-free expansion media with VEGF, Flt-3 ligand, TPO, IL-6, and SCF. The vascular regeneration capability of MNC-QQ cells pre- or post-QQc was evaluated with an EPC colony-forming assay, FACS, EPC culture, tube formation assay, and quantitative real time PCR. For in vivo assessment, 1 × 10 pre- and post-MNC-QQc cells from diabetic donors were injected into a murine wound-healing model using Balb/c nude mice. The percentage of wound closure and angio-vasculogenesis was then assessed. This study revealed vasculogenic, anti-inflammatory, and wound-healing effects of MNC-QQ therapy in both in vitro and in vivo models. This system addresses the low efficiency and efficacy of the current naïve MNC therapy for wound-healing in diabetic patients. As this technique requires a simple blood draw, isolation, and peripheral blood MNC suspension culture for only a week, it can be used as a simple and effective outpatient-based vascular and regenerative therapy for patients with diabetes mellitus.
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http://dx.doi.org/10.1002/sctm.20-0309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133343PMC
June 2021

Quality and Quantity-Cultured Human Mononuclear Cells Improve Human Fat Graft Vascularization and Survival in an In Vivo Murine Experimental Model.

Plast Reconstr Surg 2021 02;147(2):373-385

From the Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine; and the Department of Plastic and Reconstructive Surgery, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel.

Background: Fat graft ischemia impedes us from having satisfying long-term results. The quality and quantity culture is a 1-week cell culture that increases the vasculogenic potential of peripheral blood mononuclear cells (PBMNC). This in vivo murine model investigates whether enrichment with quality and quantity-cultured human mononuclear cells (MNC-QQ) improves the vascularization in the human fat graft and whether this decreases the tissue loss.

Methods: Human adipose tissue, PBMNC, MNC-QQ, and stromal vascular fraction were prepared. First, PBMNC, MNC-QQ, and stromal vascular fraction were compared in vitro for vasculogenic potential by endothelial progenitor cell colony-forming and culture assays. Second, 0.25-g fat grafts were created with 1 × 106 PBMNC (n = 16), 1 × 106 MNC-QQ (n = 16), 1 × 106 stromal vascular fraction (n = 16), or phosphate-buffered saline as control (n = 16) before grafting in BALB/c nude mice. Grafts were analyzed for weight persistence, vessel formation by CD31 immunohistochemistry, and angiogenic markers by quantitative polymerase chain reaction.

Results: MNC-QQ develop more definitive endothelial progenitor cell colonies and more functional endothelial progenitor cells compared to PBMNC and stromal vascular fraction. Weight persistence after 7 weeks was significantly higher in grafts with MNC-QQ (89.8 ± 3.5 percent) or stromal vascular fraction (90.1 ± 4.2 percent) compared with control (70.4 ± 6.3 percent; p < 0.05). MNC-QQ-enriched grafts had the highest vessel density (96.6 ± 6.5 vessels/mm2; control, 70.4 ± 5.6 vessels/mm2; p < 0.05). MNC-QQ exerted a direct vasculogenic effect through vascular integration and a potential paracrine vascular endothelial growth factor-mediated effect.

Conclusion: Quality and quantity-cultured human mononuclear cells containing endothelial progenitor cells stimulate fat graft vascularization and enhance graft survival in a rodent recipient.
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http://dx.doi.org/10.1097/PRS.0000000000007580DOI Listing
February 2021

Keloid patients have higher peripheral blood endothelial progenitor cell counts and CD34 cells with normal vasculogenic and angiogenic function that overexpress vascular endothelial growth factor and interleukin-8.

Int J Dermatol 2019 Dec 9;58(12):1398-1405. Epub 2019 Jul 9.

Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan.

Background: One suggested reason for aberrant wound healing in keloid scars is chronic inflammation of the dermis. We hypothesized that excessive blood vessel formation and high capillary density in keloid tissue is caused by dysfunction of endothelial progenitor cells.

Methods: We compared the number of circulating endothelial progenitor cells and vasculogenic and angiogenic capacity, as well as secretory function, of circulating CD34 cells in keloid patients and healthy individuals.

Results: Compared to mononuclear cell cultures from healthy donors, cultures of peripheral blood mononuclear cells obtained from keloid patients showed a more than twofold increase in the number of peripheral blood EPCs (fibronectin-adhering cells that phagocytized acetylated low-density lipoprotein and bound Ulex europaeus agglutinin-I lectin). However, there was no difference in colony-forming ability and participation in in vitro angiogenesis between circulating CD34 cells isolated from keloid patients and healthy individuals. This means that circulating CD34 /endothelial progenitor cells in keloid patients have normal vasculogenic and angiogenic function. However, CD34 cells derived from keloid patients demonstrated a more than sevenfold expression of the interleukin-8 gene and a more than fivefold expression of the vascular endothelial growth factor gene than CD34 cells derived from healthy individuals.

Conclusions: These results support the role of vascular endothelial growth factor and interleukin-8 in increased recruitment of endothelial progenitor cells in keloid patients.
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http://dx.doi.org/10.1111/ijd.14575DOI Listing
December 2019

Quality and Quantity-Cultured Murine Endothelial Progenitor Cells Increase Vascularization and Decrease Fibrosis in the Fat Graft.

Plast Reconstr Surg 2019 Apr;143(4):744e-755e

From the Plastic and Reconstructive Surgery Department, Juntendo University School of Medicine; and the Plastic and Reconstructive Surgery Department, Universitair Ziekenhuis Brussel (University Hospital Brussels), Vrije Universiteit Brussel.

Background: Fat grafting has become a valuable technique for soft-tissue reconstruction; however, long-lasting success depends on several determinants. An early blood supply to the transplanted adipocytes is important to prevent ischemia. The recently developed quality and quantity (QQ) culture increases the vasculogenic potential of endothelial progenitor cells. The authors used a murine fat grafting model to address the hypothesis that QQ-cultured endothelial progenitor cells stimulate the establishment of a blood vessel network and increase graft success.

Methods: c-KitSca-1Lin (KSL) cells were isolated as endothelial progenitor cell precursors from C57BL/6 mice. Adipose tissue was grafted with QQ-cultured KSL cells (QQKSL group), uncultured KSL cells (KSL group), adipose-derived stem cells (ASC group), and a combination (QQKSL+ASC group), and compared to a control group. Five and 10 weeks later, grafts were weighed, histologic and immunohistochemical parameters were evaluated, and gene expression was quantified by quantitative polymerase chain reaction.

Results: The highest vessel density was observed in the combined QQKSL+ASC group (68.0 ± 4.3/mm; p < 0.001) and the QQKSL group (53.9 ± 3.0/mm; p < 0.001). QQKSL cells were engrafted in proximity to the graft vasculature. QQKSL cells decreased the fibrosis percentage (13.8 ± 1.8 percent; p < 0.05). The combined QQKSL+ASC group (22.4 ± 1.8/mm; p < 0.001) showed the fewest local inflammation units. A significant up-regulation of platelet-derived growth factor and adiponectin expression was observed in the QQKSL group and QQKSL+ASC group. Graft weight persistence was not significantly different between groups.

Conclusions: Supplementing fat grafts with quality and quantity-cultured endothelial progenitor cells improves graft quality by stimulating vascularization. The increased vessel density is associated with less fibrosis, less inflammation, and better adipose tissue integrity. Enriching fat grafts with QQ-cultured endothelial progenitor cells is a potential solution to their clinical shortcomings.
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http://dx.doi.org/10.1097/PRS.0000000000005439DOI Listing
April 2019

Effectiveness of endothelial progenitor cell culture under microgravity for improved angiogenic potential.

Sci Rep 2018 09 24;8(1):14239. Epub 2018 Sep 24.

Department of Plastic and Reconstructive Surgery, School of Medicine, Juntendo University, Tokyo, Japan.

Endothelial progenitor cell (EPC) transplantation is beneficial for ischemic diseases such as critical limb ischemia and ischemic heart disease. The scarcity of functional EPCs in adults is a limiting factor for EPC transplantation therapy. The quality and quantity culture (QQc) system is an effective ex vivo method for enhancing the number and angiogenic potential of EPCs. Further, microgravity environments have been shown to enhance the functional potential of stem cells. We therefore hypothesized that cells cultured with QQc under microgravity may have enhanced functionality. We cultured human peripheral blood mononuclear cells using QQc under normal (E), microgravity (MG), or microgravity followed by normal (ME) conditions and found that ME resulted in the most significant increase in CD34+ and double positive Dil-Ac-LDL-FITC-Ulex-Lectin cells, both EPC markers. Furthermore, angiogenic potential was determined by an EPC-colony forming assay. While numbers of primitive EPC-colony forming units (pEPC-CFU) did not change, numbers of definitive EPC-CFU colonies increased most under ME conditions. Gene-expression profiling also identified increases in angiogenic factors, including vascular endothelial growth factor, under MG and ME conditions. Thus, QQc along with ME conditions could be an efficient system for significantly enhancing the number and angiogenic potential of EPCs.
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http://dx.doi.org/10.1038/s41598-018-32073-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155294PMC
September 2018

Human peripheral blood mononuclear cells enriched in endothelial progenitor cells via quality and quantity controlled culture accelerate vascularization and wound healing in a porcine wound model.

Cell Transplant 2018 07 5;27(7):1068-1079. Epub 2018 Jul 5.

1 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

The transplantation of endothelial progenitor cells (EPCs) is used to promote wound angiogenesis. In patients with chronic wounds and accompanying morbidities, EPCs are often compromised in number and function. To overcome these limitations, we previously developed a quality and quantity controlled (QQ) culture system to enrich peripheral blood mononuclear cells (PBMNCs) in EPCs. To evaluate the wound healing efficacy of mononuclear cells (MNCs) harvested after QQ culture (QQMNCs), preclinical studies were performed on large animals. MNCs harvested from the blood of healthy human subjects were cultured in the presence of angiogenic cytokines and growth factors in a serum-free medium for 7 days. A total of 5 × 10 QQMNCs per full-thickness skin defect or control saline was injected into wounds induced in cyclosporine-immunosuppressed pigs. EPC colony-forming assays revealed a significantly higher number of definitive (partially differentiated) EPC colony-forming units in QQMNCs. Flow cytometry evaluation of QQMNC surface markers showed enrichment of CD34 and CD133 stem cell populations, significant reduction in CCR2 cell percentages, and a greater than 10-fold increase in the percentage of anti-inflammatory M2-type macrophages (CD206 cells) compared with PBMNCs. Wounds treated with QQMNCs had a significantly higher closure rate. Wounds were harvested, frozen, and sectioned at day 21 postoperatively. Hematoxylin and eosin staining revealed that the epithelization of QQMNC-treated wounds was more advanced than in controls. Treated wounds developed granulation tissue with more mature collagen and larger capillary networks. CD31 and human mitochondrial co-staining confirmed the presence of differentiated human cells within newly formed vessels. Real-time polymerase chain reaction (PCR) showed upregulation of interleukin 6 (IL-6), IL-10, and IL-4 in the wound bed, suggesting paracrine activity of the transplanted QQMNCs. Our data demonstrate for the first time that QQ culture of MNCs obtained from a small amount of peripheral blood yields vasculogenic and therapeutic cells effective in wound healing.
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http://dx.doi.org/10.1177/0963689718780307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158547PMC
July 2018

Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice.

Cell Transplant 2018 03 8;27(3):520-530. Epub 2018 May 8.

5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan.

Acute kidney injury (AKI) is a major clinical problem that still has no established treatment. We investigated the efficacy of cultured human peripheral blood mononuclear cells (PBMNCs) for AKI. Ischemia/reperfusion injury (IRI) was used to induce AKI in male nonobese diabetic (NOD/severe combined immunodeficiency) mice aged 7 to 8 wk. PBMNCs were isolated from healthy volunteers and were subjected to quality and quantity controlled (QQc) culture for 7 d in medium containing stem cell factor, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin 6. IRI-induced mice were divided into 3 groups and administered (1) 1 × 10 PBMNCs after QQc culture (QQc PBMNCs group), (2) 1 × 10 PBMNCs without QQc culture (non-QQc PBMNCs group), or (3) vehicle without PBMNCs (IRI control group). PBMNCs were injected via the tail vein 24 h after induction of IRI, followed by assessment of renal function, histological changes, and homing of injected cells. Blood urea nitrogen and serum creatinine (Cr) 72 h after induction of IRI in the QQc PBMNCs group dramatically improved compared with those in the IRI control and the non-QQc PBMNCs groups, accompanied by the improvement of tubular damages. Interstitial fibrosis 14 d after induction of IRI was also significantly improved in the QQc PBMNCs group compared with the other groups. The renoprotective effect noted in the QQc PBMNCs group was accompanied by reduction of peritubular capillary loss. The change of PBMNCs' population (increase of CD34+ cells, CD133+ cells, and CD206+ cells) and increased endothelial progenitor cell colony-forming potential by QQc culture might be one of the beneficial mechanisms for restoring AKI. In conclusion, an injection of human QQc PBMNCs 24 h after induction of IRI dramatically improved AKI in mice.
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http://dx.doi.org/10.1177/0963689717753186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038042PMC
March 2018

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells.

Stem Cells Transl Med 2018 05 24;7(5):428-438. Epub 2018 Mar 24.

Department of Basic Clinical Science, Division of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.

Autologous endothelial progenitor cell (EPC) therapy is commonly used to stimulate angiogenesis in ischemic repair and wound healing. However, low total numbers and functional deficits of EPCs make autologous EPC therapy ineffective in diabetes. Currently, no known ex vivo culture techniques can expand and/or ameliorate the functional deficits of EPCs for clinical usage. Recently, we showed that a quality-quantity culture (QQc) system restores the vasculogenic and wound-healing efficacy of murine diabetic EPCs. To validate these results and elucidate the mechanism in a translational study, we evaluated the efficacy of this QQc system to restore the vasculogenic potential of diabetic human peripheral blood (PB) CD34+ cells. CD34+ cells purified from PB of diabetic and healthy patients were subjected to QQc. Gene expression, vascular regeneration, and expression of cytokines and paracrine mediators were analyzed. Pre- or post-QQc diabetic human PB-CD34+ cells were transplanted into wounded BALB/c nude mice and streptozotocin-induced diabetic mice to assess functional efficacy. Post-QQc diabetic human PB-CD34+ cell therapy significantly accelerated wound closure, re-epithelialization, and angiogenesis. The higher therapeutic efficacy of post-QQc diabetic human PB-CD34+ cells was attributed to increased differentiation ability of diabetic CD34+ cells, direct vasculogenesis, and enhanced expression of angiogenic factors and wound-healing genes. Thus, QQc can significantly enhance the therapeutic efficacy of human PB-CD34+ cells in diabetic wounds, overcoming the inherent limitation of autologous cell therapy in diabetic patients, and could be useful for treatment of not only wounds but also other ischemic diseases. Stem Cells Translational Medicine 2018;7:428-438.
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http://dx.doi.org/10.1002/sctm.17-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905232PMC
May 2018

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice.

PLoS One 2017 23;12(5):e0178232. Epub 2017 May 23.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Persistent inflammatory environment and abnormal macrophage activation are characteristics of chronic diabetic wounds. Here, we attempted to characterize the differences in macrophage activation and temporal variations in cytokine expression in diabetic and non-diabetic wounds, with a focus on interleukin (IL)-6 mRNA expression and the p38 MAPK and PI3K/Akt signaling pathways. Cutaneous wound closure, CD68- and arginase-1 (Arg-1)-expressing macrophages, and cytokine mRNA expression were examined in non-diabetic and streptozotocin-induced type 1 diabetic mice at different time points after injury. The effect of IL-6 on p38 MAPK and Akt phosphorylation was investigated, and an in vitro scratch assay was performed to determine the role of IL-6 in primary skin fibroblast migration. Before injury, mRNA expression levels of the inflammatory markers iNOS, IL-6, and TNF-α were higher in diabetic mice; however, IL-6 expression was significantly lower 6 h post injury in diabetic wounds than that in non-diabetic wounds. Non-diabetic wounds exhibited increased p38 MAPK and Akt phosphorylation; however, no such increase was found in diabetic wounds. In fibroblasts from non-diabetic mice, IL-6 increased the phosphorylation of p38 MAPK and levels of its downstream factor CREB, and also significantly increased Akt phosphorylation and levels of its upstream factor P13K. These effects of IL-6 were not detected in fibroblasts derived from the diabetic mice. In scratch assays, IL-6 stimulated the migration of primary cultured skin fibroblasts from the non-diabetic mice, and the inhibition of p38 MAPK was found to markedly suppress IL-6-stimulated fibroblast migration. These findings underscore the critical differences between diabetic and non-diabetic wounds in terms of macrophage activation, cytokine mRNA expression profile, and involvement of the IL-6-stimulated p38 MAPK-Akt signaling pathway. Aberrant macrophage activation and abnormalities in the cytokine mRNA expression profile during different phases of wound healing should be addressed when designing effective therapeutic modalities for refractory diabetic wounds.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178232PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441644PMC
September 2017

Liposome-Encapsulated Hemoglobin Accelerates Skin Wound Healing in Diabetic dB/dB Mice.

Artif Organs 2017 Apr 21;41(4):319-326. Epub 2017 Mar 21.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Shinjuku, Tokyo, Japan.

Since liposome-encapsulated hemoglobin with high O affinity (h-LEH, P O  = 10 mm Hg) has been reported to accelerate skin wound healing in normal mice, it was tested in dB/dB mice with retarded wound healing, as seen in human diabetics. Two full-thickness dorsal wounds 6 mm in diameter encompassed by silicone stents were created in dB/dB mice. Two days later (day 2), the animals were randomly assigned to receive intravenous h-LEH (2 mL/kg, n = 7) or saline (2 mL/kg, n = 7). The same treatment was repeated 4 days after wounding (day 4), and the size of the skin lesions was analyzed by photography, surface perfusion was detected by Laser-Doppler imager, and plasma cytokines and chemokines were determined on days 0, 2, 4, and 7, when all animals were euthanized for morphological studies. The size of the ulcer compared to the skin defect or silicone stent became significantly reduced on days 4 and 7 in mice treated with h-LEH (47 ± 8% of original size), similar to the level in wild-type mice, compared to saline-treated dB/dB mice (68 ± 18%, P < 0.01). Mice treated with h-LEH had significantly attenuated inflammatory cytokines, increased surface perfusion, and increased Ki67 expression on day 7 in accordance with the ulcer size reduction, while there was no significant difference in chemokines, histological granulation, epithelial thickness, and granulocyte infiltration detected by immunohistochemical staining in the ulcer between the treatment groups. The results suggest that h-LEH (2 mL/kg) early after wounding may accelerate skin wound healing in dB/dB mice to levels equivalent to wild-type mice probably via mechanism(s) involving reduced hypoxia, increased surface perfusion, suppressed inflammation, accelerated in situ cell proliferation and protein synthesis.
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http://dx.doi.org/10.1111/aor.12864DOI Listing
April 2017

Application of Kuhnt-Szymanowski Procedure to Lower Eyelid Margin Defect after Tumor Resection.

Plast Reconstr Surg Glob Open 2017 Feb 22;5(2):e1230. Epub 2017 Feb 22.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.

Background: Lower eyelid reconstruction after tumor removal is always challenging, and full-thickness defects beyond half of the eyelid length require a flap from a part other than the remaining lower eyelid, such as the temporal area or the cheek.

Objective: We aimed to report our experience of applying Smith-modified Kuhnt-Szymanowski, one of the most popular procedures for paralytic ectropion, for reconstructing oblong full-thickness lower eyelid margin defect.

Materials And Methods: We performed Smith-modified Kuhnt-Szymanowski on 5 cases of oblong full-thickness lower eyelid margin defect after skin cancer removal. The mean age of patients was 80.0 years. The horizontal widths of the defects ranged from half to two-thirds of the lower eyelid length and the vertical width ranged from 5 to 9 mm.

Results: We obtained good functional and esthetic results in all cases. No patients developed ectropion or lower eyelid distortion, and all patients were satisfied with their results.

Conclusions: We utilized the procedure for morphological revision as a reconstructive procedure for eyelid margin defect by considering the defect as a morphological deformity of the eyelid margin; thus, donor tissue was not required to fill the defect and we could accomplish the reconstruction simply, firmly, and less invasively.
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http://dx.doi.org/10.1097/GOX.0000000000001230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340486PMC
February 2017

A Low-Level Carbon Dioxide Laser Promotes Fibroblast Proliferation and Migration through Activation of Akt, ERK, and JNK.

PLoS One 2017 3;12(1):e0168937. Epub 2017 Jan 3.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.

Background: Low-level laser therapy (LLLT) with various types of lasers promotes fibroblast proliferation and migration during the process of wound healing. Although LLLT with a carbon dioxide (CO2) laser was also reported to promote wound healing, the underlying mechanisms at the cellular level have not been previously described. Herein, we investigated the effect of LLLT with a CO2 laser on fibroblast proliferation and migration.

Materials And Methods: Cultured human dermal fibroblasts were prepared. MTS and cell migration assays were performed with fibroblasts after LLLT with a CO2 laser at various doses (0.1, 0.5, 1.0, 2.0, or 5.0 J/cm2) to observe the effects of LLLT with a CO2 laser on the proliferation and migration of fibroblasts. The non-irradiated group served as the control. Moreover, western blot analysis was performed using fibroblasts after LLLT with a CO2 laser to analyze changes in the activities of Akt, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), which are signaling molecules associated with cell proliferation and migration. Finally, the MTS assay, a cell migration assay, and western blot analysis were performed using fibroblasts treated with inhibitors of Akt, ERK, or JNK before LLLT with a CO2 laser.

Results: In MTS and cell migration assays, fibroblast proliferation and migration were promoted after LLLT with a CO2 laser at 1.0 J/cm2. Western blot analysis revealed that Akt, ERK, and JNK activities were promoted in fibroblasts after LLLT with a CO2 laser at 1.0 J/cm2. Moreover, inhibition of Akt, ERK, or JNK significantly blocked fibroblast proliferation and migration.

Conclusions: These findings suggested that LLLT with a CO2 laser would accelerate wound healing by promoting the proliferation and migration of fibroblasts. Activation of Akt, ERK, and JNK was essential for CO2 laser-induced proliferation and migration of fibroblasts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168937PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207507PMC
September 2017

End-to-Side Neurorrhaphy as Schwann Cells Provider to Acellular Nerve Allograft and Its Suitable Application.

PLoS One 2016 1;11(12):e0167507. Epub 2016 Dec 1.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Axonal regeneration relies on support from proliferating host Schwann cells (SCs), and previous studies on acellular nerve allografts (ANGs) suggest that axons can regenerate into ANGs within a limited distance. Numerous studies have demonstrated that the supplementation of ANGs with exogenous factors, such as cultured SCs, stem cells, and growth factors, promote nerve regeneration in ANGs. However, there are several problems associated with their utilization. In this study, we investigated whether end-to-side (ETS) neurorrhaphy, which is an axonal provider, could be useful as an SC provider to support axonal elongation in ANGs. We found that ETS neurorrhaphy effectively promoted SC migration into ANGs when an epineurium window combined with partial neurectomy was performed, and the effectiveness increased when it was applied bilaterally. When we transplanted ANGs containing migrated SCs via ETS neurorrhaphy (hybrid ANGs) to the nerve gap, hybrid ANGs increased the number of regenerated axons and facilitated rapid axonal elongation, particularly when ETS neurorrhaphy was applied to both edges of the graft. This approach may represent a novel application of ETS neurorrhaphy and lead to the development of hybrid ANGs, making ANGs more practical in a clinical setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167507PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132318PMC
June 2017

A synthetic leukotriene B receptor type 2 agonist accelerates the cutaneous wound healing process in diabetic rats by indirect stimulation of fibroblasts and direct stimulation of keratinocytes.

J Diabetes Complications 2017 01 14;31(1):13-20. Epub 2016 Sep 14.

Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo 113-8421, Japan. Electronic address:

Aims: The synthetic leukotriene B receptor type 2 (BLT2) agonist CAY10583 (CAY) accelerates wound healing in diabetic mice by promoting keratinocyte migration. However, its effects on fibroblast activity and granulation are unknown. We investigated the mechanisms by which CAY promotes wound healing.

Methods: CAY was applied to wounds on streptozotocin-induced diabetic rats, and wound closure, granulation thickness, and epithelialization gaps were analyzed. BLT2 expression was examined by RT-PCR. Migration and proliferation were studied by scratch assays and MTS assays. Keratinocyte supernatants with CAY were applied to fibroblasts, and cytokines were measured by enzyme-linked immunosorbent assays.

Results: CAY significantly accelerated wound healing in diabetic rats (CAY, 78.05±12.22% vs. control, 59.84±11.09%; p=0.0222), with increased re-epithelialization and granulation compared to controls. BLT2 was expressed in keratinocytes, but not in fibroblasts. Keratinocyte treatment with the CAY supernatant enhanced fibroblast proliferation and migration (fibroblast scratch closure: CAY, 75.95±4.09% vs. control, 49.69±4.49%; p<0.0001). CAY-treated keratinocytes exhibited increased TGF-β1 and bFGF expression.

Conclusions: CAY directly promotes keratinocyte migration and indirectly enhances fibroblast proliferation by increasing keratinocyte production of TGF-β1 and bFGF, accelerating wound closure. CAY is a promising pharmaceutical agent for diabetic wounds.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.09.002DOI Listing
January 2017

[Treatment of diabetic foot].

Nihon Rinsho 2016 Apr;74 Suppl 2:363-7

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April 2016

Levator lengthening technique using cartilage or fascia graft for paralytic lagophthalmos in facial paralysis.

J Plast Reconstr Aesthet Surg 2016 May 2;69(5):679-86. Epub 2016 Feb 2.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan.

Introduction: Lid loading using gold weights has been commonly used to treat paralytic lagophthalmos (PL); however, the procedure has a relatively high complication rate and the availability of these plates varies among social circumstances. We used a levator lengthening (LL) technique, which originally elongated the levator aponeurosis by inserting a fascia graft between the edge of the levator aponeurosis and the tarsal plate. However, because this procedure tends to result in a wide residual lagophthalmos, we changed the graft material from fascia to conchal cartilage. In this study, we describe in detail our experience with LL using the cartilage graft.

Methods: LL was performed in 18 patients with PL. Fascia grafts were used in seven patients and cartilage grafts in 11. Static reconstructions of the lower eyelid and eyebrow were also performed in most patients. Efficacy was evaluated from patient reports of ocular symptoms and by measuring the palpebral fissure width at opening and closing for both eyes.

Results: All patients experienced improved ophthalmological symptoms, which were more apparent in cartilage cases. The average palpebral fissure at eyelid closure was 1.8 mm in cartilage cases and 4.0 mm in fascia cases. In cases where an eyebrow lift was concurrently performed, the residual lagophthalmos became wider in fascia grafting but remained acceptable in cartilage grafting.

Discussion: LL is a simple and useful procedure for treating PL with higher efficacy when a cartilage graft is used. However, the level of the upper eyelid can be easily adjusted by changing the fixation position of the cartilage. Additional experience is required to obtain more consistent outcomes.
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http://dx.doi.org/10.1016/j.bjps.2016.01.010DOI Listing
May 2016

Effectiveness of platysma muscle flap in preventing Frey syndrome and depressive deformities after parotidectomy.

J Plast Reconstr Aesthet Surg 2016 May 18;69(5):663-72. Epub 2016 Jan 18.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.

Background: Frey syndrome (FS) or depressive deformity (DD) occurring after parotidectomy significantly reduces a patient's quality of life. However, there seems to be no effective treatment strategy against these complications. In this study, we report our experience of using platysma muscle flap (PMF) to prevent the development of FS and DD after parotidectomy, and evaluate its effect subjectively and objectively.

Methods: Superficial parotidectomy was performed for eight cases of parotid gland tumor, and a PMF was transferred to cover the site. The incidence of FS and DD were evaluated subjectively, using a questionnaire to the patients and board-certified reconstructive surgeons, and objectively, using Minor's starch-iodine test.

Results: In seven patients, the defect could be completely covered with PMF, and none of them developed FS or obvious DD. However, in one patient, the defect could be only partially covered, and the patient developed complications in the exact site that the flap did not cover. Overall scores from the questionnaire were high in relation to both cosmetic and functional perspectives from most of the patients and all the surgeons. No patients had major postoperative complications requiring revision.

Conclusions: PMF can be useful to cover the defect and prevent complications after parotidectomy. PMF is relatively easy to perform with fewer complications; however, a complete coverage of the defect should be ensured to obtain optimal results.
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http://dx.doi.org/10.1016/j.bjps.2015.12.021DOI Listing
May 2016

Assessment of T-shape double fascia graft for lower lip deformity from facial paralysis: A questionnaire survey.

J Plast Reconstr Aesthet Surg 2016 Mar 19;69(3):427-35. Epub 2015 Nov 19.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan.

Introduction: There are two main methods to treat lower-lip deformity (LLD) in facial paralysis. The first method is surgical intervention on the side of the paralysis, and the second involves denervating the depressor muscles on the healthy side. It is sometimes difficult for patients to ethically accept the denervating healthy tissue; therefore, we performed the T-shape double fascia graft (TSDFG), which reportedly restores symmetry. In this study, we report our experience with TSDFG and evaluation of the outcomes including the patient questionnaires.

Methods: Two fascia strips from the thigh, 7 × 70 mm in size, were used; one was grafted horizontally at the lower lip to correct the static position, and the other was grafted obliquely at the lateral side by folding and crossing the horizontal fascia. A total of nine patients were treated by this procedure; three procedures were performed individually and six were performed in combination with another static or reanimation procedure. A questionnaire containing a five-point scoring system for facial appearance in multiple situations and other problems was sent to each patient at least 6 months after the surgery.

Result: From the physicians' point of view, all patients achieved an improvement in symmetry of the lower lip, particularly when opening of the mouth; however, assessments from the patients demonstrated much less satisfaction. The main reason for the dissatisfaction was the slight bulkiness of the red lip. There was one comment that noted that with more treatment, the expectations were higher, and, as a result, the patient could not admit satisfaction at the end.

Discussion: TSDFG is a simple and effective procedure for LLD; however, slight modifications may be required. In addition, there were some gaps in the perception of the results between the physicians and patients, and we need to consider these when planning to treat LLD.
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http://dx.doi.org/10.1016/j.bjps.2015.10.032DOI Listing
March 2016

The role of Notch signaling in diabetic endothelial progenitor cells dysfunction.

J Diabetes Complications 2016 Jan-Feb;30(1):12-20. Epub 2015 Sep 30.

Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address:

Aims: To investigate the role of Notch signaling pathway in vasculogenic dysfunction of diabetic EPCs (DM-EPCs).

Methods: The study was performed in mice and diabetes was induced with Streptozotocin. The functional consequences of Notch pathway modulation were studied by assessment of colony forming capacity (EPC colony forming assay), EPC differentiation capacity (% of definitive EPC-CFU (dEPC-CFU)), circulating EPCs (EPC culture assay) and migrated cells (migration assay); in the presence of Notch inhibitor (γ-secretase inhibitors (GSI)) compared to control. Notch pathway and VEGF involvement in DM- EPCs were assessed by gene expression (RT-qPCR).

Results: DM demonstrated to increase Notch pathway expression in bone marrow (BM) EPCs followed by lower EPC-CFU number, EPCs differentiation capacity, number of circulating EPCs, migrated cells and VEGF expression compared to control (p<0.05). Inhibition of Notch pathway by GSI rescued vasculogenic dysfunction in DM-EPCs as represented by increase in EPC-CFU number, differentiation capacity and number of circulating EPCs (p<0.05).

Conclusion: Our findings indicate the involvement of Notch pathway in mediating DM-EPCs dysfunction including less number of EPC-CFU, circulating EPCs and migrated cell number compared to control. Further in vitro inhibition of Notch pathway by GSI rescued DM-EPC dysfunction. Therefore targeting Notch pathway in DM may provide a target to restore DM-EPC dysfunction.
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http://dx.doi.org/10.1016/j.jdiacomp.2015.09.015DOI Listing
October 2016

Coadministration of adipose-derived stem cells and control-released basic fibroblast growth factor facilitates angiogenesis in a murine ischemic hind limb model.

J Vasc Surg 2016 Dec 17;64(6):1825-1834.e1. Epub 2015 Nov 17.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan. Electronic address:

Objective: Adipose-derived stem cells (ASCs) have angiogenic potential owing to their differentiation into endothelial cells and their release of angiogenic growth factors to elicit paracrine effects. In addition, control-released basic fibroblast growth factor (bFGF) sustained with a gelatin hydrogel also supports effective angiogenesis. We sought to determine if coadministration of ASCs and control-released bFGF into murine ischemic limbs facilitates angiogenesis.

Methods: Levels of growth factors in the conditioned media of ASCs cultured with or without control-released bFGF were measured by enzyme-linked immunosorbent assays. A murine ischemic hind limb model was generated and intramuscularly injected with the following: gelatin hydrogel (group 1), a high number of ASCs (group 2), control-released bFGF (group 3), a small number of ASCs and control-released bFGF (group 4), and a high number of ASCs and control-released bFGF (group 5). Macroscopic and microscopic vascular changes were evaluated until day 7 by laser Doppler perfusion imaging and histologic analyses, respectively.

Results: Secretion of hepatocyte growth factor, vascular endothelial growth factor, and transforming growth factor-β1 was enhanced by control-released bFGF. Vascular improvement was achieved in groups 4 and 5 according to laser Doppler perfusion imaging. Hematoxylin and eosin staining and CD31 immunohistochemical staining demonstrated an increase in the vascular density, vessel diameter, and thickness of vessel walls in groups 4 and 5. Cells positively stained for CD146, α-smooth muscle actin, and transforming growth factor-β1 were observed around vessel walls in groups 4 and 5.

Conclusions: These findings suggest that coadministration of ASCs and control-released bFGF facilitates angiogenesis in terms of vessel maturation in a murine ischemic hind limb model.
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http://dx.doi.org/10.1016/j.jvs.2015.09.054DOI Listing
December 2016

The availability of perifascial areolar tissue graft for deep cutaneous ulcer coverage.

J Plast Reconstr Aesthet Surg 2015 Dec 19;68(12):1743-9. Epub 2015 Aug 19.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Soft tissue defects or skin ulcers associated with tendon or bone exposure located distally on the extremities are always difficult to treat. The introduction of the vacuum-assisted closure (VAC) and dermal templates has led to major changes in ulcer treatment strategies. However, it is necessary to find an alternative method to treat these defects when VAC is not available. Perifascial areolar tissue (PAT) is the loose connective tissue on the deep fascia that could be a candidate for repairing soft tissue defects or skin ulcers. Grafting PAT on the exposed bone or tendon, including a wide coverage of well-vascularized tissue surrounding the granulation tissue, can prepare the wound to be subsequently closed by a skin graft. In this study, the PAT was used in various situations and its optimal usage and outcomes were evaluated. A total of 13 PAT grafts were performed and were especially useful for covering narrow ulcers with narrow tendon exposure and filling fistula areas. In comparison to other cases, covering the exposed cortical bone ulcers seemed to be more difficult to perform. However, an option for these ulcers could be the exposure of bone marrow and usage of intraosseous blood flow. It was also possible for the simultaneous engraftment of PAT and skin in narrow areas and could be an alternative in cases of small concave ulcers or fistulae. The PAT graft is a simple and minimally invasive procedure that can be a good alternative when VAC is not available.
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http://dx.doi.org/10.1016/j.bjps.2015.08.008DOI Listing
December 2015

Introduction to next generation of endothelial progenitor cell therapy: a promise in vascular medicine.

Am J Transl Res 2015 15;7(3):411-21. Epub 2015 Mar 15.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine Tokyo, Japan.

The concept of Endothelial Progenitor Cells (EPCs) therapy for adult neovascularization has continuously received attention. They are believed to participate in endothelial repair and post natal angiogenesis due to their abilities in differentiating into endothelial cells and producing protective cytokines and growth factors. Abundant evidence supports the involvement of EPCs in capillary growth and in participating in the formation of collateral vessels, which lead to improved vascular perfusion and functional recovery in target tissue. Autologous EPC now is becoming a novel treatment option for therapeutic revascularization and vascular repair in ischemic diseases. However, various diseases such as diabetes, heart disease and ischemic diseases are related to EPC dysfunction and give rise to additional challenges of autologous EPC therapy. A novel strategy to enhance the number and function of EPCs is needed to be established to provide successful autologous EPCs therapy. Currently, clinical trials for the new generation of EPC therapy in treating peripheral ischemic diseases are underway. In this review we provide an overview and the limitations of current EPCs therapy with an introduction to the new strategies of next generation EPC therapy for more promising vascular and tissue regeneration therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448183PMC
June 2015

Massive myoepithelial carcinoma originating from the submandibular gland that was successfully treated with surgical excision, using a part of the lengthened skin as a local flap.

Plast Reconstr Surg Glob Open 2015 Mar 7;3(3):e329. Epub 2015 Apr 7.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan; Department of Otolaryngology-Head and Neck Surgery, Moriyama Memorial Hospital, Tokyo, Japan; Department of Plastic and Reconstructive Surgery, Kawasakinanbu Hospital, Kanagawa, Japan; Department of Ear, Nose, and Throat, Juntendo University School of Medicine, Tokyo, Japan; and Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Myoepithelial carcinoma is rare and mostly originates from the major salivary glands. Sometimes, it is difficult to differentiate the benign from the malignant histologically, and its clinical behavior and histological features may vary. Here, we describe the case of a 55-year-old woman who presented with a massive myoepithelial carcinoma, which hung like a temple bell from her right side of the jaw, and she refused to go to the hospital for 3 years. Based on its size and location, we initially thought that, before surgical resection, neoadjuvant therapy would be necessary to reduce the tumor volume. However, after careful evaluation of the tumor characteristics (low-grade histology with outward expansion and little invasion of the adjacent tissues) and imaging findings, we decided that excision was possible. The tumor was encapsulated and had a clear border; it weighed 10.5 kg. By setting the incision line posterior to the equatorial plane and using the lengthened skin posterior to the tumor as a large local flap for the skin defect, we successfully reconstructed the skin defect without harvesting additional flap from other areas. No additional treatment was administered because a sufficient surgical margin was maintained, pathologically. She regained her daily life without recurrence or distant metastasis for 2 years. When treating a massive tumor, careful consideration of its characteristics and location is important, and in this case, we were able to use a simpler and less invasive treatment than we initially envisioned.
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http://dx.doi.org/10.1097/GOX.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387151PMC
March 2015

Conjunctival Squamous Cell Carcinoma due to Long-term Placement of Ocular Prosthesis.

Plast Reconstr Surg Glob Open 2015 Mar 7;3(3):e325. Epub 2015 Apr 7.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan; Department of Plastic and Reconstructive Surgery, Juntendo University Sizuoka Hospital, Sizuoka, Japan; and Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Conjunctival squamous cell carcinoma (SCC) arising from an anophthalmic socket is quite rare, with few reports in the English literature. A 59-year-old man who had used an ocular prosthesis for 40 years had not removed the ocular prosthesis at all during the last 5 years. He had developed a mass on his entire right upper eyelid, and biopsy revealed a moderately differentiated SCC. Orbital exenteration including the upper and lower eyelid skin was performed. The defect was reconstructed with a free forearm flap followed by the placement of a facial epithesis. The pathology revealed an intraepithelial carcinoma on the upper palpebral conjunctiva, which seemed to infiltrate exclusively from that site to the upper eyelid and into the orbit. Other risk factors were not detected; therefore, chronic irritation or microtrauma of the upper conjunctiva from the prosthesis due to persistent prosthesis placement could have been the main trigger for the development of SCC. In cases where the ocular prosthesis is not fitted properly or removed appropriately, clinicians should be aware of this possible long-term consequence.
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http://dx.doi.org/10.1097/GOX.0000000000000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387147PMC
March 2015

Intraoperative Use of Indocyanine Green Fluorescence Angiography during Distally Based Radial Artery Perforator Flap for Squamous Cell Carcinoma of the Thumb.

Plast Reconstr Surg Glob Open 2015 Feb 6;3(2):e310. Epub 2015 Mar 6.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan; Department of Plastic and Reconstructive Surgery, Kawasakinanbu Hospital, Kanagawa, Japan; and Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Distally based radial artery perforator flap (DBRAPF) is useful for hand defects; however, the location of the perforator varies among individuals. Preoperative evaluation has been a problematic issue when performing this flap. A 64-year-old man developed squamous cell carcinoma on an old burn scar at the dorsal thumb and was referred to our clinic for further treatment. After wide resection of the tumor, including the long and short extensors of the thumb, we reconstructed the defect with DBRAPF. At that time, near-infrared fluorescence angiography with indocyanine green (ICG) was used to identify the position of the perforator. After injecting ICG intravenously, we could observe its uptake at approximately 5 cm proximal to the styloid process. We designed a 10 × 6 cm island flap with that uptake as pivot point. During flap elevation, the perforator could be confirmed at the point of uptake; the flap was then transferred to the defect by rotating the pedicle at the identified point. The vascularity of the flap could also be checked intraoperatively through ICG angiography. The tip of the flap that showed weak ICG fluorescence indicated epidermal necrosis. Nevertheless, the entire flap was viable and enabled good functionality without tumor recurrence and metastasis after 5 years. Using ICG angiography, DBRAPF could be performed smoothly, easily, and safely.
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http://dx.doi.org/10.1097/GOX.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350316PMC
February 2015

Oxidative stress tolerance of early stage diabetic endothelial progenitor cell.

Regen Ther 2015 Jun 23;1:38-44. Epub 2015 Feb 23.

Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

Introduction: One of the causes for poor vasculogenesis of diabetes mellitus (DM) is known to rise from the dysfunction of bone marrow-derived endothelial progenitor cells (BM EPCs). However, the origin of its cause is less understood. We aimed to investigate the effect of oxidative stress in early stage of diabetic BM-EPC and whether its vasculogenic dysfunction is caused by oxidative stress.

Methods: Bone marrow c-Kit+Sca-1+Lin- (BM-KSL) cells were sorted from control and streptozotocin-induced diabetic C57BL6J mice by flow cytometry. BM-KSLs were then assessed for vasculogenic potential (colony forming assay; EPC-CFA), accumulation of intracellular ROS (CM-H2DCFDA), carbonylated protein (ELISA), anti-oxidative enzymes expression (RT-qPCR) and catalase activity (Amplex Red).

Results: Compared to control, DM BM-KSL had significantly lower EPC-CFUs in both definitive EPC-CFU and total EPC-CFU (p < 0.05). Interestingly, the oxidative stress level of DM BM-KSL was comparable and was not significantly different to control followed by increased in anti-oxidative enzymes expression and catalase activity.

Conclusions: Primitive BM-EPCs showed vasculogenic dysfunction in early diabetes. However the oxidative stress is not denoted as the major initiating factor of its cause. Our results suggest that primitive BM-KSL cell has the ability to compensate oxidative stress levels in early diabetes by increasing the expression of anti-oxidative enzymes.
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http://dx.doi.org/10.1016/j.reth.2014.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581786PMC
June 2015

Endogenous cell therapy improves bone healing.

J Craniofac Surg 2015 Jan;26(1):300-5

From the *Department of Plastic Surgery, Institute of Reconstructive Plastic Surgery Laboratories, New York University Medical Center, New York, New York; and †Juntendo University School of Medicine, Department of Plastic and Reconstructive Surgery, Tokyo, Japan.

Background: Although bone repair is often a relatively rapid and efficient process, many bone defects do not heal. Because an adequate blood supply is essential for new bone formation, we hypothesized that augmenting new blood vessel formation by increasing the number of circulating vasculogenic progenitor cells (PCs) with AMD3100 and enhancing their trafficking to the site of injury with recombinant human parathyroid hormone (rhPTH) will improve healing.

Methods: Critical-sized 3-mm cranial defects were trephined into the right parietal bone of C57BLKS/J 6 mice (N = 120). The mice were divided into 4 equal groups (n = 30 for each). The first group received daily subcutaneous injections of AMD3100 (5 mg/kg). The second group received daily subcutaneous injections of rhPTH (5 mg/kg). The third group received both AMD3100 and rhPTH. The fourth group received subcutaneous injections of saline. Circulating vasculogenic PC numbers, new blood vessel formation, and bony regeneration were assessed. Progenitor cell adhesion, migration, and tubule formation were assessed in the presence of rhPTH and AMD3100.

Results: Flow cytometry demonstrated that combination therapy significantly increased the number of circulating PCs compared with all other groups. In vitro, AMD3100-treated PCs had significantly increased adhesion migration, and tubule formation was assessed in the presence of rhPTH. Combination therapy significantly improved new blood vessel formation in those with cranial defect compared with all other groups. Finally, bony regeneration was significantly increased in the combination therapy group compared with all other groups.

Conclusions: The combination of a PC-mobilizing and traffic-enhancing agent improved bony regeneration of calvarial defects in mice.
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http://dx.doi.org/10.1097/SCS.0000000000001306DOI Listing
January 2015
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