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Sulfur mustard (SM)-induced ocular injury is characterized by an acute inflammatory response that may become chronic or enter a latent phase with delayed pathology. This study aimed to evaluate the efficacy of ziv-aflibercept and aflibercept in preventing and ameliorating corneal neovascularization (NV), respectively, following chemical eye exposure to SM vapor in a rabbit model. Chemical SM ocular insult was induced in the right eye of rabbits. A single application of ziv-aflibercept was administered 2 h or 9 days post-exposure. A single subconjunctival aflibercept treatment in an ocular formulation was administered 4 weeks after SM vapor exposure and subsequent to an initial 1-week treatment with 0.1 % dexamethasone. Clinical monitoring was performed 5-12 weeks post-exposure, and digital corneal pictures were taken to assess the extent of NV. The rabbits were euthanized and the corneas were processed for histological assessment. Treatment with ziv-aflibercept 2 h and 9 days post-exposure moderately reduced insult severity and partially delayed or prevented corneal NV. Aflibercept application 4 weeks post-exposure significantly reduced the extent of NV for 8 weeks. The substantial decrease in existing corneal NV in this group was confirmed by histology. These results reveal the powerful anti-angiogenic efficacy of the VEGF-trap for ameliorating existing NV as opposed to preventing NV development, revealing the ability of this treatment to mitigate corneal NV.
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Nanoparticle technologies offer a non-invasive means to deliver basic fibroblast growth factor (bFGF) for the treatment of spinal cord injury (SCI). However, the inability of bFGF to accumulate at the injury site and inefficient penetration across the blood-spinal cord barrier (BSCB) remain challenges. The present study describes a dual-targeting liposome (bFGF@Lip-Cp&Rp) with injury lesion targeting and BSCB-penetrating capability to deliver bFGF for SCI treatment. The CAQK peptide (Cp) with injury lesion targeting ability and R2KC peptide (Rp) with BSCB-penetrating capability were grafted onto the liposomes for a flexible and non-invasive drug delivery systems preparation. Results exhibit that the dual-targeted liposomes could significantly cross the BSCB and accumulate at the injury site. During the early stage of SCI, bFGF@Lip-Cp&Rp promotes repair of BSCB and facilitates M2-polarization of macrophages. Regular delivery of bFGF@Lip-Cp&Rp increase HUVECs tube formation and angiogenesis, ameliorate the microenvironment of lesion site, suppress the neuronal apoptosis and axonal atrophy in SCI rats. Importantly, continuous treatment of bFGF@Lip-Cp&Rp supports the restoration of limb motor function in SCI rats. In summary, this research implies that the injury site-targeting and BSCB-penetrating liposomes could be a promising therapeutic approach for the treatment of SCI.
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Intervertebral disc degeneration (IDD)-induced low back pain significantly influences the quality of life, placing a burden on public health systems worldwide. Currently available therapeutic strategies, such as conservative or operative treatment, cannot effectively restore intervertebral disc (IVD) function. Decellularized matrix (DCM) is a tissue-engineered biomaterial fabricated using physical, chemical, and enzymatic technologies to eliminate cells and antigens. By contrast, the extracellular matrix (ECM), including collagen and glycosaminoglycans, which are well retained, have been extensively studied in IVD regeneration. DCM inherits the native architecture and specific-differentiation induction ability of IVD and has demonstrated effectiveness in IVD regeneration in vitro and in vivo. Moreover, significant improvements have been achieved in the preparation process, mechanistic insights, and application of DCM for IDD repair. Herein, we comprehensively summarize and provide an overview of the roles and applications of DCM for IDD repair based on the existing evidence to shed a novel light on the clinical treatment of IDD.
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For traditional artificial dermises, a waiting period of approximately three weeks is required after the first implantation before they are adequately vascularized. The objective of this retrospective case series was to investigate whether full-thickness skin defects, requiring surgical reconstruction, could be successfully treated by implantation of a basic fibroblast growth factor (bFGF)-impregnated artificial dermis and secondary skin grafting with a shorter waiting period. Between January 2019 and January 2021, 19 skin defects in 14 patients (7 male and 7 female) were treated with two-stage skin grafting using bFGF-impregnated collagen-gelatin sponge (CGS). All of them were included in this case series, and the waiting period for skin grafting, success rate of skin grafting, infection during the waiting period, and scar quality 6-12 months postoperatively were retrospectively investigated. As a result, all skin grafting surgeries were successfully performed with a waiting period of 13.3 ± 4.3 days. Infection during the waiting period was observed in three lesions (15.8%); however, all infections were controllable. Postoperative scar quality was acceptable (Vancouver Scar Scale score range, 1-8). In conclusion, compared to traditional artificial dermises, bFGF-impregnated CGSs have the potential to shorten the waiting period without decreasing the success rate of skin grafting. Further studies are required to confirm this finding.
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Introduction: This study included patients who underwent full-thickness skin reconstruction using a two-stage procedure comprising basic fibroblast growth factor-impregnated collagen gelatin sponge (bFGF-CGS) implantation and autologous skin grafting, and the take rate of skin grafts was compared between groups of patients who underwent autologous skin grafting after a waiting period of <2 weeks or ≥2 weeks. Methods: An acute, full-thickness skin defect was treated with thorough debridement of contaminated/necrotic tissue, followed by washing with saline and hemostasis with electrocautery. Then, an FGF-CGS was fixed to the skin defect wound using non-absorbable sutures, and after confirming regeneration of sufficient dermis-like tissue, the second-stage autologous skin grafting was performed for wound closure. Patients were divided into two groups according to the waiting period before the second operation, namely, <2 weeks (early group) and ≥2 weeks (late group), and the take rate of skin grafts was compared. Results: We enrolled and treated 25 cases (18 men, 7 women; mean age: 49 [range 2-86] years). The mean take rate of skin grafts was 93% (range 80%-100%) in the early group and 92% (range 65%-100%) in the late group, with no significant difference between the two groups. There was a significant difference between the groups in mean time to complete healing: 25.2 ± 9.7 days in the early group vs 44.7 ± 27 days in the late group (p < 0.05). Conclusion: Our data suggest that bFGF-CGF can form dermis-like granulation tissue with sufficient quality as a graft bed for skin transplantation within 2 weeks.
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Skin manifestations of systemic disorders give a clue to the organ involved and help identify the possible disease-causing injury. Skin changes of liver cirrhosis are not specific, as they may be seen in disorders not involving the liver. Thus, a constellation of skin changes along with systemic features may help us to identify the disease-causing liver cirrhosis. Pruritus is one of the most common and distressful symptoms of liver cirrhosis, severely affecting the quality of life, which further necessitates understanding cutaneous manifestations of cirrhosis. Other nonspecific cutaneous manifestations include spider telangiectasia, palmar erythema, paper money skin, xanthomas, pigmentation changes, nutritional deficiencies, hair changes, and nail changes. This review discusses the nonspecific skin manifestations associated with liver cirrhosis followed by specific cutaneous findings seen in common diseases causing liver cirrhosis, such as viral infections, biliary tract disorders, chronic alcoholism, and metabolic disorders. Early recognition of cutaneous features can help prevent or delay the development of complications and end-stage disease, decreasing morbidity and mortality.
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Cancer immunotherapy has become a new generation of anti-tumor treatment, but its indications still focus on several types of tumors that are sensitive to the immune system. Therefore, effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy. Natural products are reported to have this effect on cancer immunotherapy, including cancer vaccines, immune-check points inhibitors, and adoptive immune-cells therapy. And the mechanism of that is mainly attributed to the remodeling of the tumor-immunosuppressive microenvironment, which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy. Therefore, this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism. And we found that saponins, polysaccharides, and flavonoids are mainly three categories of natural products, which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment. Besides, this review also collected the studies about nano-technology used to improve the disadvantages of natural products. All of these studies showed the great potential of natural products in cancer immunotherapy.
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The pandemic of the coronavirus disease 2019 (COVID-19) has made biotextiles, including face masks and protective clothing, quite familiar in our daily lives. Biotextiles are one broad category of textile products that are beyond our imagination. Currently, biotextiles have been routinely utilized in various biomedical fields, like daily protection, wound healing, tissue regeneration, drug delivery, and sensing, to improve the health and medical conditions of individuals. However, these biotextiles are commonly manufactured with fibers with diameters on the micrometer scale (> 10 µm). Recently, nanofibrous materials have aroused extensive attention in the fields of fiber science and textile engineering because the fibers with nanoscale diameters exhibited obviously superior performances, such as size and surface/interface effects as well as optical, electrical, mechanical, and biological properties, compared to microfibers. A combination of innovative electrospinning techniques and traditional textile-forming strategies opens a new window for the generation of nanofibrous biotextiles to renew and update traditional microfibrous biotextiles. In the last two decades, the conventional electrospinning device has been widely modified to generate nanofiber yarns (NYs) with the fiber diameters less than 1000 nm. The electrospun NYs can be further employed as the primary processing unit for manufacturing a new generation of nano-textiles using various textile-forming strategies. In this review, starting from the basic information of conventional electrospinning techniques, we summarize the innovative electrospinning strategies for NY fabrication and critically discuss their advantages and limitations. This review further covers the progress in the construction of electrospun NY-based nanotextiles and their recent applications in biomedical fields, mainly including surgical sutures, various scaffolds and implants for tissue engineering, smart wearable bioelectronics, and their current and potential applications in the COVID-19 pandemic. At the end, this review highlights and identifies the future needs and opportunities of electrospun NYs and NY-based nanotextiles for clinical use.
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Background: Basic fibroblast growth factor (bFGF)-mediated vascular smooth muscle cell (VSMC) proliferation and migration play an important role in vascular injury-induced neointima formation and subsequent vascular restenosis, a major event that hinders the long-term success of angioplasty. The function of ß3-adrenergic receptors (ß3-ARs) in vascular injury-induced neointima formation has not yet been defined. Objectives: Our current study explored the possible role of ß3-ARs in vascular injury-induced neointima formation by testing its effects on bFGF-induced VSMC migration and proliferation. Methods: ß3-AR expression in rat carotid arteries was examined at 14 days following a balloon catheter-induced injury. The effects of ß3-AR activation on bFGF-induced rat aortic smooth muscle cell proliferation, migration, and signaling transduction (including extracellular-signal-regulated kinase/mitogen activated protein kinase, ERK/MAPK and Protein kinase B, AKT) were tested. Results: We found that vascular injury induced upregulation of ß3-ARs in neointima. Pretreatment of VSMCs with a selective ß3-AR agonist, CL316,243 significantly potentiated bFGF-induced cell migration and proliferation, and ERK and AKT phosphorylation. Our results also revealed that suppressing phosphorylation of ERK and AKT blocked bFGF-induced cell migration and that inhibiting AKT phosphorylation reduced bFGF-mediated cell proliferation. Conclusion: Our results suggest that activation of ß3-ARs potentiates bFGF-mediated effects on VSMCs by enhancing bFGF-mediated ERK and AKT phosphorylation and that ß3-ARs may play a role in vascular injury-induced neointima formation.
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Osteosarcoma frequently presents as recurrence and metastasis, even if the primary lesion was eradicated and/or radiotherapy and chemotherapy were administered. Osteosarcoma cancer stem cells (CSCs) are one of the key factors for the recurrence and metastasis of osteosarcoma. We have shown that interleukin-24 (IL-24) inhibits osteosarcoma cell proliferation, migration and invasion in vitro. In the current study, we investigated the role of IL-24 in inhibiting the growth of osteosarcoma CSCs. IL-24 inhibited proliferation and invasion and decreased the stemness of osteosarcoma CSCs in vitro. In a nude mouse xenograft model, IL-24 significantly inhibited the growth of tumors originating from osteosarcoma CSCs. Moreover, we found that IL-24 was able to inactivate both Notch and Wnt/ß-Catenin signaling, which are important for the development of the biological characteristics of CSCs. These data demonstrate that IL-24 is able to kill not only cancer cells but also CSCs in osteosarcoma, suggesting that IL-24 might eradicate osteosarcoma and enhance long-term cure rates in patients with osteosarcoma.
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INTRODUCTION: The objective of this study is to investigate the effect of gelatin microspheres incorporating growth factors on the therapeutic efficacy in cell transplantation. The strength of this study is to combine gelatin hydrogel microspheres incorporating basic fibroblast growth factor and platelet growth factor mixture (GM/GF) with bioabsorbable injectable hydrogels (iGel) for transplantation of adipose-derived stem cells (ASCs). METHODS: The rats ASCs suspended in various solutions were transplanted in masseter muscle. Rats were euthanized 2, 7, 14 days after injection for measurement of the number of ASCs retention in the muscle and morphological evaluation of muscle fibers and the inflammation of the injected tissue by histologic and immunofluorescent stain. RESULTS: Following the injection into the skeletal muscle, the GM/GF allowed the growth factors to release at the injection site over one week. When ASCs were transplanted into skeletal muscle using iGel incorporating GM/GF (iGel+GM/GF), the number of cells grafted was significantly high compared with other control groups. Moreover, for the groups to which GM/GF was added, the cells transplanted survived, and the Myo-D expression of a myoblast marker was observed at the region of cells transplanted. CONCLUSIONS: The growth factors released for a long time likely enhance the proliferative and differentiative capacity of cells. The simple combination with iGel and GM/GF allowed ASCs to enhance their survival at the injected site and consequently achieve improved therapeutic efficacy in cell transplantation.
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Treatment of burn injuries with Mesenchymal stem cells (MSCs) is a great promise due to their unique properties. As two natural and functional wound dressing, Chitosan and Aloe-Vera gel assist wound regeneration by providing a proper environment. In the current study, we aimed to compare the effect of encapsulated BMSCs in Chitosan-based gel and Aloe-Vera gel on the healing of grade-II burn injuries compared to other groups in the rat. After creation of a 2 × 2 cm grade-II burn on dorsal skin of rats, treatments were performed for each group. The wound closure rate and healing properties were evaluated by histopathological analysis on 7, 14, 21 and, 28 days post-treatment. The expression rate of VEGF, Collagen-I and Collagen-III genes was also assessed on days 3, 7, 14, 21 and 28 performing qRT-PCR. The full wound healing with inconsiderable scar formation was achieved for Aloe-vera/BMSCs and Chitosan/BMSCs group on 28th day post-treatment. Pathological results also demonstrated the highest angiogenesis and granulation tissue formation for Aloe-vera/BMSCs and Chitosan/BMSCs groups respectively. The expression level of VEGF, Collagen-I, and Collagen-III genes was significantly higher in these groups on days 14 and 21, compared to other groups. Results demonstrated the synergistic effect of BMSCs when combined with Chitosan or Aloe-vera gel enhanced the healing process of wound healing more than chitosan gel treatment. Therefore, this gel can be considered as effective approaches for treatment of burn injuries.
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Series of sulfonated polymers were evaluated as additives in cell culture media. Some of the compounds, such as sulfated polyvinyl alcohol (PVA), prevented denaturation and loss of basic fibroblast growth factor during cell culture and enhanced human mesenchymal stem cell proliferation. These compounds are xeno-free alternatives of heparin, an animal-derived sulfated saccharide, often used as an additive. To the best our knowledge, this study is the first to show that chemically defined synthetic chemicals, such as sulfated polyvinyl alcohol, can be used for this purpose.
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Reconstruction of long-bone segmental defects (LBSDs) has been one of the biggest challenges in orthopaedics. Biomaterials for the reconstruction are required to be strong, osteoinductive, osteoconductive, and allowing for fast angiogenesis, without causing any immune rejection or disease transmission. There are four main types of biomaterials including autograft, allograft, artificial material, and tissue-engineered bone. Remarkable progress has been made in LBSD reconstruction biomaterials in the last ten years. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our aim is to summarize recent developments in the divided four biomaterials utilized in the LBSD reconstruction to provide the clinicians with new information and comprehension from the biomaterial point of view.
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INTRODUCTION: Basic fibroblast growth factor (bFGF) is a promising cytokine in regenerative therapy for spinal cord injury. In this study, recombinant canine bFGF (rc-bFGF) was synthesized for clinical use in dogs, and the ability of rc-bFGF to differentiate canine bone marrow mesenchymal stem cells (BMSCs) into functional neurons was investigated. METHODS: The rc-bFGF was synthesized using a wheat germ cell-free protein synthesis system. The expression of rc-bFGF mRNA in the purification process was confirmed using a reverse transcription-polymerase chain reaction (RT-PCR). Western blotting was performed to confirm the antigenic property of the purified protein. To verify function of the purified protein, phosphorylation of extracellular signal-regulated kinase (ERK) was examined by in vitro assay using HEK293 cells. To compare the neuronal differentiation capacity of canine BMSCs in response to treatment with rc-bFGF, the cells were divided into the following four groups: control, undifferentiated, rh-bFGF, and rc-bFGF groups. After neuronal induction, the percentage of cells that had changed to a neuron-like morphology and the mRNA expression of neuronal markers were evaluated. Furthermore, to assess the function of the canine BMSCs after neuronal induction, changes in the intracellular Ca2+ concentrations after stimulation with KCl and l-glutamate were examined. RESULTS: The protein synthesized in this study was rc-bFGF and functioned as bFGF, from the results of RT-PCR, western blotting, and the expression of pERK in HEK293 cells. Canine BMSCs acquired a neuron-like morphology and expressed mRNAs of neuronal markers after neuronal induction in the rh-bFGF and the rc-bFGF groups. These results were more marked in the rc-bFGF group than in the other groups. Furthermore, an increase in intracellular Ca2+ concentrations was observed after the stimulation of KCl and l-glutamate in the rc-bFGF group, same as in the rh-bFGF group. CONCLUSIONS: A functional rc-bFGF was successfully synthesized, and rc-bFGF induced the differentiation of canine BMSCs into voltage- and glutamate-responsive neuron-like cells. Our purified rc-bFGF may contribute, on its own, or in combination with canine BMSCs, to regenerative therapy for spinal cord injury in dogs.
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INTRODUCTION: Growth factors are crucial bioactive molecules in vitro and in vivo. Among them, basic fibroblast growth factor (bFGF) has been used widely for various applications such as cell culture and regenerative medicine. However, bFGF has extremely poor stability in aqueous solution; thus, it is difficult to maintain its high local concentration. Heparin-conjugated materials have been studied recently as promising scaffold-immobilizing growth factors for biological and medical applications. The previous studies have focused on the local concentration maintenance and sustained release of the growth factors from the scaffold. METHODS: In this paper, we focused on the biological stability of bFGF immobilized on the heparin-conjugated collagen (hep-col) scaffold. The stability of the immobilized bFGF was quantitatively evaluated at physiological temperature (37 °C) using cell culture and ELISA. RESULTS: The immobilized bFGF had twice higher stability than the bFGF solution. Furthermore, the hep-col scaffold was able to immobilize not only bFGF but also other growth factors (i.e., vascular endothelial growth factor and hepatocyte growth factor) at high efficiency. CONCLUSIONS: The hep-col scaffold can localize several kinds of growth factors as well as stabilize bFGF under physiological temperature and is a promising potent scaffold for regenerative medicine.
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Osteonecrosis of the femoral head (ONFH) is a progressive disease with a complex etiology and unclear pathogenesis, resulting in severe hip pain and dysfunction mainly observed in young patients. Although total hip arthroplasty (THA) is the most effective treatment for patients with ONFH in the terminal stage, the results of THA in young patients or active populations are often not favorable, with some complications related to the prosthesis. With the development of biotechnology, an increasing number of studies pay attention to use of stem cells for the treatment of ONFH. Stem cells are characterized by the ability to self-renew and differentiate into multiple cell types, including differentiation into osteoblasts and endothelial cells to mediate bone repair and angiogenesis. Furthermore, stem cells can offer growth factors to promote blood supply in the necrotic regions by paracrine effects. Therefore, stem cell therapy has become one of the hip-preserving alternatives for ONFH. This review summarized the current trends in stem cell therapy for ONFH, from clinical applications to related basic research, and showed that an increasing number of studies have confirmed the effectiveness of stem cell therapy in ONFH. However, many unsolved problems and challenges in practical applications of stem cell therapy still exist, such as patient selection, standardized procedures, safety assessment, and the fate of transplanted cells in the body. Additional studies are required to find ideal cell sources, appropriate transplantation methods, and the optimal number of cells for transplantation.
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INTRODUCTION: The definitive treatment for severe heart failure is transplantation. However, only a small number of heart transplants are performed each year due to donor shortages. Therefore, novel treatment approaches based on artificial organs or regenerative therapy are being developed as alternatives. We have developed a technology known as cell sheet-based tissue engineering that enables the fabrication of functional three-dimensional (3D) tissue. Here, we report a new technique for engineering human cardiac tissue with perfusable blood vessels. Our method involved the layering of cardiac cell sheets derived from human induced pluripotent stem cells (hiPSCs) on a vascular bed derived from porcine small intestinal tissue. METHODS: For the vascular bed, a segment of porcine small intestine was harvested together with a branch of the superior mesenteric artery and a branch of the superior mesenteric vein. The small intestinal tissue was incised longitudinally, and the mucosa was resected. Human cardiomyocytes derived from hiPSCs were co-cultured with endothelial cells and fibroblasts on a temperature-responsive dish and harvested as a cardiac cell sheet. A triple-layer of cardiac cell sheets was placed onto the vascular bed, and the resulting construct was subjected to perfusion culture in a bioreactor system. RESULTS: The cardiac tissue on the vascular bed pulsated spontaneously and synchronously after one day of perfusion culture. Electrophysiological recordings revealed regular action potentials and a beating rate of 105 ± 13/min (n = 8). Furthermore, immunostaining experiments detected partial connection of the blood vessels between the vascular bed and cardiac cell sheets. CONCLUSIONS: We succeeded in engineering spontaneously beating 3D cardiac tissue in vitro using human cardiac cell sheets and a vascular bed derived from porcine small intestine. Further development of this method might allow the fabrication of functional cardiac tissue that could be used in the treatment of severe heart failure.
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INTRODUCTION: This study examined the usefulness of basic fibroblast growth factor impregnated collagen-gelatin sponge (bFGF-CGS) in reconstructive surgery for various acute skin defects including deep dermal burns, facial full-thickness skin defects, and finger amputations as the first clinical application. METHODS: Reconstructive surgery was performed in two stages with bFGF-CGS in 8 male subjects, ranging in age from 6 to 84 years, with acute full-thickness skin defects. Following the adequate debridement of the defect, surgeons prepared a bFGF-CGS with bFGF solution at a dose of 7-14 mg/cm2 approximately 10 min just before application and then secured the bFGF-CGS in place with non-absorbable sutures. Second-stage wound closure was performed with autologous skin grafting following adequate dermis-like tissue regeneration at the site postoperatively. Follow-up was continued for 6 months. RESULTS: Of the 8 subjects, the mean duration from the adequate vascularization of the dermis-like tissue until the second-stage autologous skin graft was 22 ± 4 days. Wound closure was achieved in all cases; the mean duration until wound closure was 32 ± 8 days. During the 6-month follow-up period, no wound infection, recurrent skin ulceration, and no exposure of tendon, bone, and cartilage were observed, and there were no cases of indirectly restricted range of motion from postoperative scar contracture and none with disfiguring scars. CONCLUSION: The authors achieved favorable outcomes following reconstructive surgery with a hybrid artificial dermis impregnated with bFGF for treating acute full-thickness skin defects. bFGF-CGS serves as a convenient regenerative device requiring no specialized medical facilities.