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Cell Therapy for Wound Healing

In covering wounds, efforts should include utilization of the safest and least invasive methods with goals of achieving optimal functional and cosmetic outcome. The recent development of advanced wound healing technology has triggered the use of cells to improve wound healing conditions. The purpose of this review is to provide information on clinically available cell-based treatment options for healing of acute and chronic wounds. Compared with a variety of conventional methods, such as skin grafts and local flaps, the cell therapy technique is simple, less time-consuming, and reduces the surgical burden for patients in the repair of acute wounds. Cell therapy has also been developed for chronic wound healing. By transplanting cells with an excellent wound healing capacity profile to chronic wounds, in which wound healing cannot be achieved successfully, attempts are made to convert the wound bed into the environment where maximum wound healing can be achieved. Fibroblasts, keratinocytes, adipose-derived stromal vascular fraction cells, bone marrow stem cells, and platelets have been used for wound healing in clinical practice. Some formulations are commercially available. To establish the cell therapy as a standard treatment, however, further research is needed. Graphical Abstract

Treatment of diabetic foot ulcers using cultured allogeneic keratinocytes—A pilot study

Diabetic foot ulcers often pose a difficult treatment problem. Repeated applications of cell‐based products have been reported to result in acceleration of diabetic wound healing. The purpose of this clinical trial study was to report preliminary findings of the efficacy and safety of the cultured allogeneic keratinocyte sheets in the treatment of diabetic foot ulcers. Fifty‐nine patients with diabetic foot ulcers were randomized to either the keratinocyte treatment group (n = 27) or the control group treated with vaseline gauze (n = 32). Except for the application of keratinocytes, treatment of study ulcers was identical for patients in both groups. Either keratinocyte sheet or vaseline gauze was applied at the beginning of the study and weekly thereafter for a maximum of 11 weeks. The maximum follow‐up period for each patient was 12 weeks. Complete ulcer healing was achieved in 100% of the treatment group and 69% of the control group (p < 0.05). The Kaplan–Meier median times to complete closure were 35 and 57 days for the keratinocyte and control groups, respectively. No adverse events related to the treatment occurred. These results indicate that cultured allogeneic keratinocytes may offer a safe and effective treatment for diabetic foot ulcers.

Randomised controlled clinical trial for autologous fibroblast-hyaluronic acid complex in treating diabetic foot ulcers

OBJECTIVE Diabetic foot ulcers (DFUs) often pose a treatment problem. Bioengineered skin substitutes have been reported to result in accelerated diabetic wound healing. The purpose of this clinical trial was to evaluate the efficacy and safety of the autologous fibroblast-hyaluronic acid complex for treating DFUs. METHOD A stratified, randomised, controlled, multicentre study was carried out. Patients with DFUs were allocated to either a treatment group with grafting of an autologous fibroblast-hyaluronic acid complex or a control group with non-adherent foam dressing. Except for application of the fibroblast complex, treatment of the study ulcers was identical for patients in both groups. The maximum follow-up period for each patient was 12 weeks. RESULTS Complete ulcer healing was achieved in 84% (26/31 patients) of the treatment group and 34% (11/32 patients) of the control group (p<0.05). The times required for complete healing were 36.4 ± 17.6 and 48.4 ± 13.1 days in the treatment and control groups, respectively (p<0.05). No adverse events related to treatment occurred. CONCLUSION These results indicate that autologous fibroblast-hyaluronic acid complex may offer a safe and effective treatment for DFUs.

Comparison of four different lasers for acne scars: Resurfacing and fractional lasers.

BACKGROUND Acne scars are common and cause cosmetic problems. There is a multitude of treatment options for acne scars, including dermabrasion, chemical peeling, and fillers, but the advent of laser technology has greatly improved the treatment of acne scars. Although several laser systems are available, studies comparing their efficacy are limited. This study compares the results of treatments using resurfacing (carbon dioxide, CO2; erbium-doped yttrium aluminum garnet, Er:YAG) versus fractional (nonablative fractional laser, NAFL; ablative fractional laser, AFL) lasers. METHODS A retrospective photographic analysis of 58 patients who underwent laser treatment for facial atrophic acne scars was performed. Clinical improvement was assessed by six blinded investigators with a scale graded from 0 to 10. Adverse events were also noted. RESULTS Mean improvement scores of the CO2, Er:YAG, NAFL, and AFL groups were 6.0, 5.8, 2.2, and 5.2, respectively. The NAFL group showed a significantly lower score than the other groups. The mean number of treatments was significantly greater in the fractional laser groups than in the resurfacing laser groups. The resurfacing laser groups had a prolonged recovery period and high risk of complications. The Er:YAG laser caused less erythema or pigmentation compared to the CO2 laser. CONCLUSIONS Although the CO2 laser, Er:YAG laser, and AFL improved the acne scars, the CO2 laser had a greater downtime. Three consecutive AFL treatments are as effective as a single treatment with resurfacing lasers, with shorter social downtime periods and less adverse effects.

Clinical and radiological outcomes of transoral endoscope-assisted treatment of mandibular condylar fractures

Fractures of the mandibular condyle are one of the most common craniofacial fractures. However, the diagnosis and treatment of these fractures is controversial because of the multiple surgical approaches available. The purposes of this study were to identify surgery-related technical tips for better outcomes and to evaluate the results as well as complications encountered during 7 years of endoscope use to supplement the limited intraoral approach in the treatment of mandibular condylar fractures. Between 2005 and 2012, 50 patients with condylar fractures underwent endoscope-assisted reduction surgery. Postoperative facial bone computed tomography and panoramic radiography demonstrated adequate reduction of the condylar fractures in all patients. No condylar resorption was detected, and most patients displayed a satisfactory functional and structural recovery. There was no facial nerve damage or transitory hypoesthesia, and there were no visible scars after the surgery. Transoral endoscope-assisted treatment is a challenging but reliable method with lower morbidity and a rapid recovery.

Wound-healing potential of human umbilical cord blood-derived mesenchymal stromal cells in vitro--a pilot study.

BACKGROUND AIMS Our previous studies demonstrated that human bone marrow-derived mesenchymal stromal cells have great potential for wound healing. However, it is difficult to clinically utilize cultured stem cells. Recently, human umbilical cord blood-derived mesenchymal stromal cells (hUCB-MSCs) have been commercialized for cartilage repair as a first cell therapy product that uses allogeneic stem cells. Should hUCB-MSCs have a superior effect on wound healing as compared with fibroblasts, which are the main cell source in current cell therapy products for wound healing, they may possibly replace fibroblasts. The purpose of this in vitro study was to compare the wound-healing activity of hUCB-MSCs with that of fibroblasts. METHODS This study was particularly designed to compare the effect of hUCB-MSCs on diabetic wound healing with those of allogeneic and autologous fibroblasts. Healthy (n = 5) and diabetic (n = 5) fibroblasts were used as the representatives of allogeneic and autologous fibroblasts for diabetic patients in the control group. Human UCB-MSCs (n = 5) were used in the experimental group. Cell proliferation, collagen synthesis and growth factor (basic fibroblast growth factor, vascular endothelial growth factor and transforming growth factor-β) production were compared among the three cell groups. RESULTS Human UCB-MSCs produced significantly higher amounts of vascular endothelial growth factor and basic fibroblast growth factor when compared with both fibroblast groups. Human UCB-MSCs were superior to diabetic fibroblasts but not to healthy fibroblasts in collagen synthesis. There were no significant differences in cell proliferation and transforming growth factor-β production. CONCLUSIONS Human UCB-MSCs may have greater capacity for diabetic wound healing than allogeneic or autologous fibroblasts, especially in angiogenesis.

Stabilizing Morbidity and Predicting the Aesthetic Results of Radial Forearm Free Flap Donor Sites.

Background The radial forearm flap is a versatile, widely used flap. However, the possibility of donor site complications has led to concern over its use. Some surgeons prefer using other flaps whose donor sites can be closed primarily with less morbidity, including avoiding unpleasant scarring. However, in our experience, donor site stability of the radial forearm flap can be reliably achieved by using well-implemented specific procedures. Here, we present a collection of donor site cases of the radial forearm flap and investigate factors that affect the aesthetic results as the basis for a reference for selecting a radial forearm flap. Methods In this retrospective study, we reviewed 171 cases in which a radial forearm flap was used for free tissue transfer after resecting head and neck cancer. We focused on donor site morbidity rates. Each operation involved a detailed procedure designed to minimize donor site morbidity. Moreover, statistical investigations were conducted for 22 cases to determine factors affecting the scar appearance. Results Only one case developed total skin graft necrosis as a major complication. Scar-related aesthetic results were acceptable, and the body-mass index, body weight, diabetes, and cardiac problems were significant factors related to the appearance of scars. Conclusions Performing the radial forearm flap using a well-implemented detailed technique helps achieve acceptable donor site morbidity results. The aesthetic results were more promising for patients without excess body weight, diabetes, or cardiac problems. Therefore, anxiety about donor site morbidity should not be a reason to avoid selecting the radial forearm flap in suitable patients.

Precaruncular approach for the reconstruction of medial orbital wall fractures.

AbstractTo reconstruct medial orbital wall fractures with a clear, least dissection, an alternative method, precaruncular approach, has been performed. We reviewed 36 patients with medial blowout fractures treated with this technique. The incision was made between the caruncle and medial canthal skin at the mucocutaneous junction, and was continued along the conjunctival fornix superiorly and inferiorly. An extended conjunctival incision was carried for additional access to the orbit floor. The dissection continued medially and proceeded along the preseptal plane. The clinical results were assessed by postoperative computed tomographic scan and by reviewing postoperative complications. Postoperatively, computed tomographic scans demonstrated adequate reduction of soft tissues and correct positioning of the inserted implant without surgical complications. In most cases, the edema resolved within 24 to 48 hours after surgery. The precaruncular approach is a good option in reconstructing medial orbital wall fractures because it provides satisfactory exposure with superior cosmetic result.

Endoscope-assisted transoral fixation of mandibular condyle fractures: Submandibular versus transoral endoscopic approach

AbstractIn recent years, endoscope-assisted transoral approach for condylar fracture treatment has attracted much attention. However, the surgical approach is technically challenging: the procedure requires specialized instruments and the surgeons experience a steep learning curve. During the transoral endoscopic (TE) approach several instruments are positioned through a narrow oral incision making endoscope maneuvering very difficult. For this reason, the authors changed the entry port of the endoscope from transoral to submandibular area through a small stab incision. The aim of this study is to assess the advantage of using the submandibular endoscopic intraoral approach (SEI).The SEI approach requires intraoral incision for fracture reduction and fixation, and 4 mm size submandibular stab incision for endoscope and traction wires. Fifteen patients with condyle neck and subcondyle fractures were operated under the submandibular approach and 15 patients with the same diagnosis were operated under the standard TE approach.The SEI approach allowed clear visualization of the posterior margin of the ramus and condyle, and the visual axis was parallel to the condyle ramus unit. The TE approach clearly shows the anterior margin of the condyle and the sigmoid notch. The surgical time of the SEI group was 128 minutes and the TE group was 120 minutes (P >0.05). All patients in the TE endoscope group were fixated with the trocar system, but only 2 lower neck fracture patients in the SEI group required a trocar. The other 13 subcondyle fractures were fixated with an angulated screw driver (P <0.05). There were no differences in complication and surgical outcomes.The submandibular endoscopic approach has an advantage of having more space with good visualization, and facilitated the use of an angulated screw driver.

Salivary Duct Carcinoma of the Deep Lobe of the Parotid Gland: A Rare Clinical Finding

Salivary duct carcinoma is a rare malignant tumor that resembles high-grade breast ductal carcinoma. It was first described by Kleinsasser et al. [1] in 1968, and is characterized by aggressive behavior, early metastasis, local recurrence, and a high mortality rate. It most commonly occurs in the parotid gland. Previously reported cases of salivary duct carcinomas involved only the superficial lobe of the parotid gland or both the superficial and deep lobes [2]. This study reports an unusual case of salivary duct carcinoma confined to the deep lobe of the parotid gland. A 59-year-old man presented with a long history of a painless lump on the left preauricular area that had gradually enlarged over the previous year. He denied pain, numbness, and facial weakness. Physical examination showed a well-defined 4×3-cm mass in the left parotid region. The mass was firm, non-compressible, and non-tender on palpation. His left facial nerve function was intact (House-Brackmann grade I). Neither cervical lymphadenopathy nor abnormalities within the oral cavity were found. Fine needle aspiration, which is not diagnostic, was not performed. Computed tomography (CT) (Fig. 1) revealed a 2.5×3.2×4.1-cm, well-enhanced, huge, lobulated, and predominantly solid tumor in the superficial lobe of the left parotid gland. The preoperative laboratory data, including electrocardiography, urinalysis, and a chest radiograph, were unremarkable. A benign tumor, such as pleomorphic adenoma, was strongly suspected, and the patient was therefore taken to the operating room with the intention of performing a left superficial parotidectomy. During the operation, the branches of the facial nerve were preserved via a modified Blair incision. Subsequently, tumor involvement in the deep parotid lobe was identified (Fig. 2). Malignancy was identified in the frozen section of a sample taken from the mass located on the deep lobe. The excision of the superficial part of the parotid gland was completed, the branches of the facial nerve were subsequently elevated, and the deep lobe of the parotid gland was resected. The lesion was classified as cT2NxM0. Fig. 1 Computed tomography scan showing a solid mass in the left parotid gland. Fig. 2 Intraoperative photograph showing the mass located on the deep lobe of the parotid gland. The forceps are shown retracting the superficial lobe. The gross specimen showed a roughly ovoid, nodular, gray-white mass with an irregular border (Fig. 3). The histology report indicated that the tumor was an invasive ductal lesion with cribriform patterns and comedonecrosis (Fig. 4). The resected superfical lobe showed a normal parotid architecture and no tumor. The final diagnosis was salivary duct carcinoma of the deep lobe of the left parotid gland. One of the surgical margins was focally positive for malignancy. No perineural invasion or lymphovascular involvement was found. Control chest CT and positron emission tomography (PET)-CT were negative. Since postoperative CT and magnetic resonance imaging revealed no definitive evidence of perineural spread or metastatic lymphadenopathy, elective neck dissection was not performed. The patient received postoperative chemoradiation therapy with 60 Gy administered in 30 fractions and biweekly cisplatin monotherapy. Following temporary facial nerve paralysis (House-Brackmann grade IV), the patient recovered fully functional left facial movement (House-Brackmann grade I) five months after the operation. He has received regular follow-up for one year with no signs of recurrence or metastasis. Fig. 3 Gross specimen of the deep lobe of the parotid gland. Fig. 4 Histological features (H&E, ×200) of salivary duct carcinoma, showing a cribriform pattern. Salivary duct carcinoma represents <1.8% of all major salivary gland tumors. It mainly affects men (73%) in their seventh decade of life. Although it predominantly arises in the parotid gland (72%), the submandibular glands and minor salivary glands may occasionally be involved [2]. It may develop on the basis of pre-existing pleomorphic adenoma in some cases (20%), but generally occurs de novo [3]. Clinically, these tumors are typically characterized by a rapidly growing mass with pain, palpable cervical lymphadenopathy, and facial nerve dysfunction. Fine needle aspiration rarely leads to a diagnosis of salivary duct carcinoma. The finding of tumoral calcifications on CT scans may be suggestive in only 33% of cases. Histologically, these tumors appear as high-grade adenocarcinoma, resembling mammary ductal carcinoma with duct formation. They are solid, with a papillary or cribriform growth pattern and intraductal comedonecrosis. Several histological variants have been described, including mucin-rich, sarcomatoid, and micropapillary types. Perineural invasion has been reported in 60% of cases, and around 30% of cases show lymphovascular invasion [3]. Although total parotidectomy with or without neck dissection and postoperative radiation therapy is the standard treatment, the local recurrence rate is high, associated with both cervical nodal involvement and distant metastasis, and resulting in a poor prognosis. Chemotherapy is generally reserved for metastatic forms [4]. Some recent studies have shown favorable treatment results using trastuzumab-based therapy. Deep lobe parotid gland tumors are rare, comprising approximately 5% of parotid gland tumors. Approximately 80%–90% of them are benign mixed tumors, such as pleomorphic adenoma, and the others are adenoid cystic, mucoepidermoid, and acinic cell carcinoma, as well as lipoma [5]. Their outward growth displaces the superficial lobe, and they therefore present as a soft preauricular mass. Deep lobe parotid tumors presenting as preauricular masses are often clinically indistinguishable from lesions of the superficial lobe, making it difficult to establish a definitive preoperative diagnosis of a lesion lying deep to the facial nerve. Based on a literature review, the salivary duct carcinoma presented in this report is unusual, because it arose in the deep lobe of the parotid gland, did not correlate with CT findings, and presented with no symptoms and an absence of perineural and lymphovascular involvement. Therefore, a better prognosis may be expected than is commonly observed in cases of salivary duct carcinoma. This case was reported because of its rarity, and also to add one more case to the existing literature on these tumors.