Therapeutic angiogenesis with intramyocardial administration of basic fibroblast growth factor

BACKGROUND: Basic fibroblast growth factor (bFGF) induces endothelial cell and smooth muscle cell proliferation and stimulates angiogenesis. This study was designed to evaluate the effects of intramyocardial administration of bFGF on myocardial blood flow, angiogenesis, and ventricular function in a canine acute infarction model. METHODS: Myocardial infarction was induced in 12 dogs by ligation of the left anterior descending coronary artery. Within 5 minutes after coronary occlusion, 100 microg of human recombinant bFGF in 1 mL of saline was injected into the infarct and border zone in 6 dogs, whereas saline alone was used in 6 control dogs. Myocardial blood flow was determined with colored microspheres before and immediately after coronary ligation and again 3, 7, 14, and 28 days after treatment and it was expressed as percent of normal. Angiogenesis was evaluated by immunohistochemical studies 28 days later. Cardiac function was evaluated by repeated echocardiographic measurement. RESULTS: Treatment with bFGF significantly increased the endocardial blood flow in the border zone (7 days after infarction, 75%+/-7% and 41% +/-7% in the bFGF and control groups, respectively, p<0.01) as well as epicardial blood flow in the infarcted zone. Treatment with bFGF significantly increased the capillary density (39.7+/-2.3 and 22.7+/-1.1 vessels per visual field in the bFGF and control groups, respectively, p<0.01) as well as arteriolar density in the border zone. Treatment with bFGF significantly reduced the change in ratio of thickness of the infarcted wall to the normal wall (44%+/-6% and 26% +/-5% in the bFGF and control groups, respectively, p<0.05). It improved the left ventricular ejection fraction (7 days after infarction, 0.54+/-0.02 and 0.37+/-0.03 in the bFGF and control groups, respectively, p<0.01). CONCLUSIONS: Intramyocardial administration of bFGF increased the regional myocardial blood flow, reduced thinning of the infarcted region, and improved ventricular function in acute myocardial infarction. Intramyocardial administration of bFGF may be a new therapeutic approach for patients with acute myocardial infarction.     

重组牛碱性成纤维细胞生长因子对手术创口愈合的影响

目的 研究重组牛碱性成纤维细胞生长因子(rbFGF）对促进手术创口愈合的影响。方法 对72例术中应用rbFGF及空白对照组的创口愈合情况进行观察，计算创口愈合所需时间，并经统计处理。结果 实验组创口甲级愈合率明显高于对照组，且愈合时间明显较对照组缩短。结论 术中使用rbFGF可以提高创口甲级愈合率，缩短手术切口愈合时间。     

Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose-response effect of basic fibroblast growth factor.

The purpose of this study was to evaluate the effects of exogenous recombinant basic fibroblast growth factor (bFGF) on angiogenesis in severely ischemic tissue beds. We used a two-stage procedure to produce severe ischemia of the hindlimb of 34 New Zealand rabbits. The ischemic hindlimb received intramuscular injection of saline (group A), 1 microgram bFGF (group B), or 3 micrograms bFGF (group C), daily for 2 weeks. Tissue perfusion, skeletal muscle infarction, angiogenesis, and collateral growth were assessed by angiography, transcutaneous oximetry (TcPO2), quantitative spectrophotometric assay of triphenyltetrazolium chloride reduction in muscle, capillary density (capillaries per square millimeter), and capillary per muscle fiber ratio. There were no significant differences in baseline TcPO2 among the three groups for both thigh and calf measurements. Angiography revealed extensive perfusion of the left hindlimb in all the assessed bFGF treated animals. Both thigh and calf TcPO2 values showed a significant increase in all groups over the 14 days ischemia was induced (p less than 0.0001), but the two treatment groups exhibited a much more rapid rise in TcPO2 than the control group (p less than 0.0001). The capillaries per square millimeter and capillaries per muscle fiber ratios were significantly increased in all posttreatment measurements for all animals that received bFGF. The treatment groups with bFGF had a significant (p = 0.025) increase in thigh muscle viability compared with controls based on triphenyltetrazolium chloride reduction. Whereas there was evidence of muscle infarction in both the thighs of groups A and B, there was none in group C.(ABSTRACT TRUNCATED AT 250 WORDS)     

新型纳米微球载碱性成纤维细胞生长因子促进新生血管形成的研究

目的 制备载碱性成纤维细胞生长因子(bFGF)甲基丙烯酸缩水甘油酯修饰葡聚糖纳米凝胶微球,观察其对新生血管生成的诱导和促进作用.方法 采用改良乳液聚合法制备载bFGF纳米微球(bFGF-Dex-GMA-NPs),对纳米微球的外形、包封率、体外释药特征进行常规检测,建立兔后肢缺血模型后,分为以下几组(每组6只):安慰剂治疗组(注射磷酸盐缓冲液)(A组);bFGF治疗组(B组);载bFGF纳米微球组(C组),分别于治疗后7、21 d用99mTc标记的sestamibi对后肢血流进行分析,并于21 d将动物处死,取局部肌肉组织切片进行免疫组织化学染色,镜下对毛细血管计数.结果 合成的纳米微球外形圆整,无相互粘连,包封率高达80.9%,并能较好地控制bFGF的释放,持续释放时间超过25 d.后肢缺血模型治疗第7天,B组和C组能量计数分别为(130.95±14.59)、(127.60±11.36),明显高于A组(27.65±6.82)(P＜0.05),但B组和C组间差异无统计学意义(P＞0.05),第21天,C组能量计数增加到(450.69±21.06),明显高于A组(39.89±8.45)和B组(165.34±15.88)(P＜0.05).免疫组织化学染色结果显示C组毛细血管密度是(99.00±5.44)/mm2,明显高于其他两组2.00±0.59(A组)、13.00±1.35(B组)(P＜0.05).结论 载bFGF纳米微球可以控制bFGF长时间释放,对缺血组织新生血管形成有优于单纯bFGF的诱导和促进作用.     

Healing large tympanic membrane perforations using hyaluronic acid, basic fibroblast growth factor, and epidermal growth factor.

Large tympanic membrane perforations usually require a surgical tympanoplasty for closure. Reducing surgical costs and risks has encouraged investigators to examine nonsurgical office procedures for healing these perforations. Growth accelerators are the most promising agents. We study here the closure of large acute perforations using weekly applications of 1 mg of 1% hyaluronic acid (HA), 0.4 microg basic fibroblast growth factor (bFGF), or 1.0 microg epidermal growth factor (EGF) directly to the tympanic membranes of the experimental ears. Control ears were treated with 0. 1 mL Vasocidin. Complete closure was obtained in 100% of the ears treated with HA and EGF and 85.7% of those treated with bFGF by day 21, compared with 63.6% of the controls by day 32. Moderate-to-severe ipsilateral and contralateral external canal hypertrophy was noted in 14.2% and 37.5% of the ears treated with bFGF and HA, respectively, but was not seen in ears treated with EGF or in the control group.     

The effect of basic fibroblast growth factor on scarring.

Granulation-tissue myofibroblasts are important in wound contraction, disappearing in normal scars but persisting in hypertrophic scars. While transforming growth factor beta 1 (TGF-beta 1) is implicated in excessive scarring and induces the accumulation of myofibroblasts, the role of basic fibroblast growth factor (FGF-2) on scarring remains unreported. Four linear full-thickness incisions, each 20 mm long, were made dorsally on 25 adult male Hooded Lister rats. In each animal, one wound was unmanipulated (control), one was injected with TGF-beta 1 (positive control), one with vehicle alone and one with FGF-2 (test). The wounds were injected daily for 5 days. Animals were sacrificed in groups of five on days 5, 10, 15, 20 and 30 after wounding. Wounds were subjected to tensiometry. Sections were stained for collagen fibres, immunostained for myofibroblasts and studied under light microscopy and electron microscopy. Myofibroblasts were present in the granulation tissue on day 5, reached their maximum number on day 10 and disappeared from all wounds by day 30. Treatment with FGF-2 inhibited this transient phenotypic change of granulation-tissue fibroblasts into myofibroblasts, relative to controls (15.23% versus 58.71%, 15.23% versus 54.71% and 15.23% versus 53.15%; P<0.003 on day 10, paired t-test). Test collagen-fibre orientation resembled that of the normal dermis, in contrast to that of the control wounds. Test wound breaking strength was unreduced. These results suggest a possible anti-scarring effect of FGF-2 during wound healing.     

Interaction of basic fibroblast growth factor with bovine growth plate chondrocytes.

The basic fibroblast growth factor (bFGF) family of peptides influences a wide range of cellular actions. To better understand the possible role of bFGF in the growth plate, we have characterized the interaction of this growth factor with isolated bovine growth plate chondrocytes. Basic FGF interacts with two classes of binding sites on these cells. One is consistent with high-affinity bFGF receptors and the other with low-affinity heparin-like binding sites on the chondrocyte surface. Radiolabeled bFGF binding studies revealed approximately 4 x 10(6) binding sites per cell, with a Kd of approximately 42 nM. Graded concentrations of heparin or NaCl competed with [125I]-labeled bFGF in a dose-dependent fashion, reducing [125I]-labeled bFGF binding by 75 and 97%, respectively. The data suggest the presence of a high-capacity, low-affinity class of binding sites with the properties of a heparin-like moiety. Affinity cross-linking of [125I]-labeled bFGF to chondrocytes labeled two principal species with apparent molecular masses of 135 and 160 kDa. Labeled bFGF was specifically displaced from both species by subnanomolar concentrations of unlabeled bFGF. These high-affinity, low-capacity binding sites are characteristic of classical bFGF receptors. Binding of [125I]-labeled bFGF to these sites was also influenced by heparin, consistent with coregulation of binding to the two classes of binding sites. The data suggest that bFGF participates in the regulation of skeletal growth at the growth plate and that this regulation may involve bFGF interaction with at least two distinct classes of binding sites.     

Effect of recombinant human basic fibroblast growth factor on angiogenesis during mandible fracture healing in rabbits

Objective: To investigate the effect of recombinant human basic fibroblast growth factor ( rhbFGF) on angiogenesis during mandible fracture healing in rabbit.Methods: Fifty adult white rabbits were used for animal model and randomly divided into a control group (25 rabbits) and an experimental group (25 rabbits). The membranous complex of rhbFGF and bovine type I collagen was prepared and implanted into the rabbit mandible fracture site under periosteum. The animals were sacrificed on 7, 14, 28, 56 and 84 days respectively after operation and the whole mandibles were harvested. The expression of factor Vm related antigen (F8-RA) in callus was examined with immimohistochemical staining.Results: The amounts of microvascular formation in calluses in the rhbFGF-treating group on days 7, 14, 28 and 56 were more than those of the control group (P < 0.01).Conclusions: The results indicated that rhbFGF could stimulate microvascular formation during mandible fracture healing in rabbits.     

Improved airway healing using basic fibroblast growth factor in a canine tracheal autotransplantation model.

OBJECTIVE: We studied 22 dogs to examine the effect of basic fibroblast growth factor (bFGF) alone, in comparison with omental or muscular wrapping on airway healing in a tracheal autotransplantation model. SUMMARY BACKGROUND DATA: Basic fibroblast growth factor is one of the most potent promoters of angiogenesis and has an ability to enhance blood supply to the ischemic airway. Topical administration of a fibrin glue enriched with 5 microg/cm2 bFGF, determined as a proportion of surface area of the tracheal grafts, improved revascularization of orthotopic canine tracheal autografts in a previous study. METHODS: All animals received orthotopic tracheal transplantation using 6-ring autografts that occupied a distal part of the thoracic trachea. Twenty-two animals were classified randomly into the following four groups: no treatment (Group G1, n = 4), muscular wrapping (Group G2, n = 4), omental wrapping (Group G3, n = 4), and topical administration of fibrin glue enriched with 5 microg/cm2 bFGF (Group G4, n = 10). Autografts were harvested 60 days after transplantation and assessed by the percent patency and histology. RESULTS: Devascularized tracheal autografts could not maintain their structural integrity without other treatments (Group G1). In contrast, more than half of all autografts receiving treatments remained viable, as demonstrated by gross and histologic findings (Groups G2, G3, and G4). Treatments with bFGF and omentum showed significantly better graft viability than no treatment. However, there was no statistical difference in the viability of tracheal autografts among the three treatment groups. In terms of the time performance ratio, bFGF was the best treatment for the devascularized autografts. CONCLUSIONS: Topical administration of bFGF was superior to the omental or muscular wrapping in terms of the time performance ratio. Clinical trials will be necessary to determine whether these findings are applicable to humans.     

Recombinant basic fibroblast growth factor accelerates wound healing

Basic fibroblast growth factor (bFGF) stimulates extracellular matrix metabolism, growth, and movement of mesodermally derived cells. We have previously shown that collagen content in polyvinyl alcohol sponges increased after bFGF treatment. We hypothesized that bFGF-treated incisional wounds would heal more rapidly. After intraperitoneal pentobarbital anesthesia, male, 200- to 250-g, Sprague-Dawley rats (n = 27) each underwent two sets of paired, transverse, dorsal incisions closed with steel sutures. On Day 3 postwounding, 0.4 ml of bFGF (recombinant, 400 ng. Synergen) or normal saline was injected into one of each paired incisions. Animals were killed with ether on postwounding Days 5, 6, and 7 and their dorsal pelts were excised. Fresh or formalin-fixed wound strips were subjected to tensile strength measurements using a tensiometer. Breaking energy was calculated. Wound collagen content (hydroxyproline) was measured in wound-edge samples following hydrolysis using high-performance liquid chromatography. There was an overall significant increase in fresh wound tensile strength (13.7 +/- 1.06 vs 19.1 +/- 1.99 g/mm, P less than 0.01) and wound breaking energy (476 +/- 47 vs 747 +/- 76 mm2, P less than 0.001) in bFGF-treated incisions. There was an increase in wound collagen content which was not statistically significant and there was no difference in fixed incisional tensile strength. Histologic examination showed better organization and maturation in bFGF wounds. Recombinant bFGF accelerates normal rat wound healing. This may be due to earlier accumulation of collagen and fibroblasts and/or to greater collagen crosslinking in bFGF-treated wounds.     

早期应用神经营养因子对周围神经损伤修复的研究观察

[目的]研究探索神经生长因子(nervegrowth factor NGF)、碱性成纤维细胞生长因子(basic fibroblast growth factor bFGF)联用对大鼠坐骨神经钳夹损伤后神经纤维再生修复的促进作用和对失神经支配的小腿三头肌的保护作用。[方法]手术钳夹损伤坐骨神经后，损伤处神经内注射NGF和bFGF，对照组注射等量生理盐水，术后每日在术侧腓肠肌内注射药物，术后4、8、12周，进行足印分析及坐骨神经功能指数测定，取小腿三头肌称湿重，取脊髓及神经肌肉行组织病理观察。[结果]联用NGF bFGF，能显著改善神经损伤后引起的神经功能指数，有效地减轻由于失神经支配后肌肉的萎缩，促进神经纤维的修复与再生。[结论]联用NGF、bFGF对大鼠坐骨神经钳夹损伤后神经纤维再生修复具有显著的促进作用，可减轻失神经支配的小腿三头肌的萎缩。     

bFGF缓释微胶囊诱导缺血心肌血管新生的实验研究

目的　探讨局部应用bFGF(碱性成纤维细胞生长因子 )缓释微胶囊对诱导缺血心肌血管新生的作用。方法　 2 4只新西兰大白兔随机分为对照组 (I组 ) ,空白胶囊组 (II组 ) ,bFGF缓释微胶囊组(III组 ,每只胶囊含bFGF 1μg) ,每组 8只。开胸结扎冠状动脉前降支根部 ,II、III组于左旋支、前降支交界区心外膜下埋藏空白微胶囊 ,或bFGF缓释微胶囊各 5只。术后 5周 ,EVAN蓝染色测定心肌梗死区与左心室重量之比 ,免疫组化测定心肌梗死边缘区微血管数。结果　与I、II组相比 ,III组心肌梗死区与左心室重量之比明显缩小 (I组 16 8%± 0 4% ,II组 16 7%± 0 5 % ,III组 7 0 %± 0 2 % ,P <0 0 0 1) ,微血管数目明显增多 (I组 37 75± 4 5 0 ,II组 38 37± 4 98,III组 135 5 0± 4 81,P <0 0 0 1)。结论　bFGF缓释微胶囊给药方便、剂量恒定 ,可以减小心肌梗死面积 ,诱导缺血心肌血管新生     

bFGF缓释微胶囊埋藏部位对兔血管新生的影响

目的：通过局部心外膜下应用碱性成纤维细胞生长因子（bFGF)缓释微胶囊，探讨春治疗心肌梗死的最佳埋藏部位，为进一步临床应用提供理论依据。方法：24只新西兰大白兔随机分为对照组（I组），空白胶囊组（Ⅱ组），bFGF缓释微胶囊组（Ⅲ组，每只胶囊含bFGF 1μg），每组8只，开胸结扎冠状动脉前降支根部，Ⅱ组、Ⅲ组于左旋支，前降支交界区心外膜下埋藏空白微胶囊，bFGF缓释微胶囊各5只。术后5周，免疫组织化学测定心肌梗死边缘区，胶囊埋藏区微血管数。结果：与I组、Ⅱ组相比较，Ⅲ组心肌梗死边缘区微血管数目明显增多（P＜0．01），胶囊埋藏区3组间微血管数差别无显著性意义（P＞0．05）。结论：bFGF缓释微胶囊组织相容性较好，在靠近缺血心肌的正常心肌心外膜下埋藏，可以达到理想的诱导缺血心肌血管新生的效果。     

Expression of basic fibroblast growth factor during distraction osteogenesis

Distraction osteogenesis is a process of tissue regeneration under an external mechanical stimulation. In the study, the spatial and temporal expression patterns of basic fibroblast growth factor in the newly formed osseous tissue during distraction osteogenesis in goats were studied using immunohistochemistry. During the distraction period, the expression of basic fibroblast growth factor was observed in the osteoblasts on the newly formed trabecular bone and the bone formation front. The cells of osteoblastic lineage and the mesenchymal cells in the distraction callus also expressed basic fibroblast growth factor. The expression of basic fibroblast growth factor in the distraction period was stronger than that during the latency and consolidation periods. However, some osteoblasts still were expressing basic fibroblast growth factor in the consolidation periods. According to these results, basic fibroblast growth factor may have a local regulatory role during distraction osteogenesis. The tensile force may stimulate the expression of basic fibroblast growth factor in osteoblasts and other cell types.     

Tissue-specific regulation of basic fibroblast growth factor mRNA levels by diabetes.

Because basic fibroblast growth factor (bFGF) is recognized as an angiogenic factor and diabetes is characterized by multiple vascular complications, including diabetic microangiopathy, we examined the regulation of tissue bFGF mRNA levels by diabetes. Diabetes was induced in male Sprague-Dawley rats by injection of 125 mg/kg body wt i.v. streptozocin (STZ), with intensive insulin therapy initiated in half of the diabetic rats. Rats were killed 96 h postinjection of STZ. Tissue bFGF and insulinlike growth factor I (IGF-I) mRNA levels were measured simultaneously with a solution hybridization-RNase protection assay. bFGF mRNA levels increased from 1.7- to 2.7-fold in eye, heart, lung, and brain from diabetic compared with buffer-injected control rats. In skeletal muscle, bFGF mRNA levels decreased to 23% of control levels, whereas bFGF mRNA levels were unchanged in kidneys from diabetic versus control rats. Changes in tissue bFGF mRNA levels were partially reversed by insulin treatment in all tissues. In contrast, IGF-I mRNA levels were significantly decreased from 15 to 50% of control levels in all tissues studied except those in brain, which decreased to only 85% of control levels. These data demonstrate that bFGF mRNA levels are altered by diabetes in a tissue-specific fashion and are consistent with the hypothesis that increased production of bFGF may contribute to the development of diabetic microangiopathy in some tissues.     

Expression of basic fibroblast growth factor in thyroid disorders

Morphologic and biologic studies were undertaken to clarify the biologic significance of basic fibroblast growth factor (bFGF) in human thyroid neoplasms. A total of 71 malignant tumors (50 papillary carcinomas, 14 follicular carcinomas, 7 anaplastic carcinomas), 11 follicular adenomas, 6 adenomatous goiters, and 6 Graves' disease tissues were examined employing immunohistochemical methods (avidin-biotin-peroxidase complex technique). An affinity-purified polyclonal rabbit antiserum to human bFGF was used as a primary antibody. The eluate of malignant thyroid tumor tissues from the heparin-Sepharose column was examined by Western blot analysis to elucidate the molecular weight form. With immunohistochemical staining, bFGF was frequently detected in the cytoplasm of malignant thyroid tumors compared to tissues of the benign diseases and normal controls. With anaplastic carcinoma, immunoreactivity of the tumor cells was particularly strong. In the correlative analyses between UICC TNM classification and bFGF staining in papillary carcinoma, there were significant differences when relating positive staining to the grade of nodal metastases. By Western blot analysis, the bFGF immunoreactivity was specifically detected in the two forms, with molecular weights of 18 and 33 kDa. The high-molecular-weight form was detected in only anaplastic carcinoma. The present investigations demonstrated a close correlation between the expression of bFGF and the degree of malignancy. bFGF might play an important role in promoting lymph node metastases. Moreover, the high-molecular-weight form of bFGF might have an intense influence on tumor growth.

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Resumen Se emprendió un estudio morfológico y biológico, con el propósito de clarificar la significación biológica del factor básico de crecimiento de fibroblastos (FBCF) en los neoplasmas de la glándula tiroides humana.Setenta y un tumores malignos (50 carcinomas papilares, 14 carcinomas foliculares y 7 carcinomas anaplásico), 11 adenomas foliculares, 6 bocios adenomatosos y 6 tejidos de glándula con enfermedad de Graves fueron examinados mediante métodos inmunohistoquímicos (técnica del complejo avidina-biotinaperoxidasa); se utilizó un antisuero policlonal purificado contra el FBCF humano, como anticuerpo primario. Además, se utilizó el análisis de Western blot para elucidar la forma de peso molecular.Con la coloración inmunohistoquímica, el FBCF fue detectado con frecuencia en el citoplasma de los tumores malignos de la tiroides, en comparación con lo observado en la enfermedad benigna y en los controles normales. La inmunorreactividad tumoral fue particulamente fuerte en el carcinoma anaplásico. En el análisis correlativo entre la clasificiación TNM UICC y la coloración del FBCF en el carcinoma papilar, se hallaron diferencias significativas relativas a la coloración positiva y al grado de la metástasis ganglionares.En el análisis Western blot, la inmunorreactividad FBCF fue específicamente detectada en las dos formas diferentes con pesos moleculares de 18 K y 33 K. La forma de alto peso molecular fue detectada sólamante en el carcinoma anaplásico.La presente investigación demuestra una estrecha correlación entre la expresión de FBCF y el grado de malignidad. El FBCF puede jugar un papel importante en promover las metástasis ganglionares. Además, la forma de alto peso molecular del FBCF puede tener una influencia más intensa sobre el crecimiento del tumor.

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Résumé Une étude morphologique et biologique a été effectuée pour clarifier la signification du facteur de croissance des fibroblastes de base (bFGF) dans les tumeurs de la thyroïde chez l'homme. On a étudié 71 tumeurs de la thyroïde (50 cancers papillaires, 14 cancers folliculaires, 6 adénomes solitaires, et 7 cancers anaplasiques, 11 adénomes folliculaires, 6 goitres adénomateux et 6 Maladies de Basedow) en utilisant des méthodes immunohistochimiques et notamment la technique du complexe avidinebiotine-peroxydase. On a employé un anticorps primaire fabriqué à partir d'un antisérum polyclonal de lapin purifié dirigé contre le bFGF humain. L'éluat des tissus thyroïdiens malins provenant de la colonne héparine-sepharose a été examiné selon la technique Western Blot pour déterminer son poids moléculaire. Le bFGF a été détecté plus fréquemment dans le cytoplasme des tumeurs thyroïdiennes malignes que dans les maladies bénignes et les contrôles. Dans le cancer anaplasique, l'immunoréactivité des cellules cancéreuses a été particulièrement forte. En ce qui concerne la corrélation entre la classification TNM de l'Union Internationale contre le Cancer et la coloration bFGF des cancers papillaires, il y avait des différences significatives correspondant au degré d'envahissement des ganglions lymphatiques. Dans l'analyse selon la technique du Western blot, l'immunoréactivité bFGF a été détectée spécifiquement sous les deux formes de bFGF ayant des poids moléculaires de 18 et de 33 K, respectivement. Le poids moléculaire de 33K n'a été détecté que dans le cancer anaplasique. Cette étude démontre la corrélation étroite entre l'expression bFGF et le degré de malignité. Le bFGF peut probablement jouer un rôle important dans la survenue de métastase lymphatique. Le type à poids moléculaire élevé de bFGF pourrait influencer d'advantage la croissance tumorale.

     

Basic fibroblast growth factor induced angiogenesis and prefabricated flap survival

Prefabrication of a latissimus dorsi myocutaneous flap was performed in adult male Landrace pigs. Gelfoam sponges were used as a delivery system for basic fibroblast growth factor (bFGF) at the muscle-subcutaneous tissue interface. Skin survival and angiogenesis were augmented in the growth-factor-treated animals. These data support the use of basic fibroblast growth factor to enhance flap prefabrication.     

Effect of transforming growth factor beta and basic fibroblast growth factor on steroid-impaired healing intestinal wounds.

A longitudinal intestinal wound model in the pig was used to assess the effect of parenteral steroids (betamethasone 12 mg 50 kg-1 intramuscularly twice daily) on breaking load. Steroid treatment significantly decreased the breaking load of wounds in the ileum and colon in comparison with wounds from saline-treated animals. In a further group of animals receiving steroids, paired longitudinal wounds were constructed. One wound of a pair was treated with a local application of transforming growth factor beta (TGF-beta) (5 micrograms per wound) or basic fibroblast growth factor (5 micrograms per wound) in a collagen suspension. The other wound was treated with a collagen suspension alone. Ileal wounds treated with TGF-beta were significantly stronger than collagen-treated controls at 7 days. The steroid-induced impairment of breaking load in intestinal wounds is partially reversed by a local application of TGF-beta in a collagen suspension at the time of surgery.     

Local delivery of basic fibroblast growth factor increases both angiogenesis and engraftment of hepatocytes in tissue-engineered polymer devices

BACKGROUND: We investigated heterotopic hepatocyte transplantation on biodegradable polymers as a potential treatment for end-stage liver disease. The primary problem has been insufficient engraftment of transplanted cells partly because of insufficient vascularization. Increasing vascularization through locally delivered angiogenic factors may increase angiogenesis and hepatocyte engraftment. METHODS: We studied the effect of local delivery of basic fibroblast growth factor (bFGF) on angiogenesis and hepatocyte engraftment within tissue-engineered liver constructs. Poly-l-lactic acid discs were fabricated and coated with either a mixture of saline, sucralfate, and Hydron (control group) or bFGF, sucralfate, and Hydron (bFGF group). bFGF release from polymers in vitro was tested using an ELISA. Hepatocytes were isolated from Lewis rats, seeded on control (n=9) or bFGF (n=11) polymers, and implanted into the small bowel mesentery of syngeneic animals. Specimens were harvested after 2 weeks and analyzed for hepatocyte engraftment. Microvascular density was compared between control (n=6) and bFGF groups (n=5). RESULTS: Three hundred twenty-three thousandths of a microgram of bFGF were incorporated per polymer. Greater than 99% of the bFGF was released into solution by 72 hr in vitro. Two weeks after implantation, microvascular density, as measured by capillaries per high-powered field (c/hpf), was significantly greater in the bFGF group (43.8 c/hpf), compared with the control group (30.5 c/hpf; P<0.005). Specimens from the bFGF group (mean engraftment, 61,355 microm2) showed a 2.5-fold increase in hepatocyte engraftment as compared with control (24,197 microm2; P<0.002). CONCLUSIONS: The angiogenic growth factor bFGF can be incorporated into degradable polymers used as delivery devices for hepatocyte transplantation. Implantation of these devices increases angiogenesis into the device and increases hepatocyte engraftment.