Growth Factors In Healing Research Articles

Scaffolds Combined with Stem Cells and Growth Factors in Healing of Pseudotumoral Lesions of Bone

Reconstructions of large lesions or defects often require a bone graft or a bone substitute to promote healing. In common practice the reconstruction of a bone defect is dependent on the site and size of the lesion: in long bones intercalary defects may be managed with Ilizarov technique of bone transport and distraction osteogenesis or the use of a free or pedicled vascularized bone graft, or with Masquelet technique. For cavitary defects the available surgical options include autograft, allograft or xenograft or the use of synthetic scaffolds to promote bone regeneration. In order to promote a faster bone healing tissue engineering proposed the application of enriched graft to fill bone defects. The employment of enriched bone graft has been our choice in the last years to fill contained defects following curettage of a pseudotumoral lesion of bone. We report our clinical experience in terms of safety and success of these procedures at a long-term follow up.

Ixodid tick salivary gland products target host wound healing growth factors

For successful blood-feeding, ticks must confront the host immune system comprising many cells and signaling molecules, mainly cytokines and growth factors. These factors bind to specific receptors on the cell membranes, thereby initiating a signaling cascade that leads to distinct cellular activities. Ticks are able to manipulate host immune responses via molecules secreted from their salivary glands. Saliva of ixodid ticks contains factors binding important cytokines and their subgroup, chemokines. Here we demonstrate that constituents of tick salivary gland extract (SGE) also appear to bind growth factors: transforming growth factor beta (TGF-β1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF-2), and hepatocyte growth factor (HGF), depending on tick species. SGE derived from Amblyommavariegatum reacted with TGF-β1, PDGF, FGF-2 and HGF; Dermacentorreticulatus and Rhipicephalusappendiculatus with TGF-β1, FGF-2 and HGF; and Ixodes ricinus and Ixodesscapularis with PDGF. SGE from the species targeting PDGF (A. variegatum and I. ricinus) also inhibited cell proliferation in vitro and induced a change in morphology of different cell lines. These effects correlated with disruption of the actin cytoskeleton. Such effects were not observed with SGE of the two species that did not target PDGF. Targeting of wound healing growth factors appears to be yet another strategy ixodid ticks adopt for suppression of inflammation and successful haematophagy.

079 An ORC/Collagen Matrix Containing Silver Preserves Wound Healing Growth Factors from Host and Bacterial Proteolytic Degradation

Chronic wounds fail to heal in the timely, ordered continuum demonstrated by acute wounds. The hostile biochemical environment of the chronic wound is one of the well-documented differences, which is thought to be responsible for the delay in healing. Overproduction of proteases, in particular matrix metalloproteinases and serine proteinases, are thought to destroy essential wound healing components including growth factors, shifting the balance in favor of tissue destruction rather than deposition. Chronic wound management must, therefore, aim to restore a more normal local wound environment. In wounds with an imbalance in bioburden, the origin of destructive enzymes may be bacterial as well as host. Therefore, treatment to achieve a biochemical balance may need to address, not only, the level of microorganism, but also, the virulent factors they produce. An ORC/collagen matrix containing silver-ORC addresses the wound microenvironment specifically targeting excess proteases. In this study we investigated the effect of ORC/collagen matrix containing silver-ORC on serine and matrix metalloproteinases, as well as, its ability to preserve growth factors, as exemplified by Platelet-Derived Growth Factor (PDGF) from host and bacterial proteolytic degradation. The ORC/collagen matrix containing silver-ORC inactivated serine and matrix metalloproteinases from chronic wound fluids, as well as the enzymes present in bacterial supernatants. It is also capable of preserving PDGF from degradation. When compared to other commonly used wound dressings this is a unique characteristic of ORC/collagen, demonstrating their exclusive ability to absorb noxious components of wound fluid and restore a more normal wound healing environment.

Synergistic action of protease-modulating matrix and autologous growth factors in healing of diabetic foot ulcers. A prospective randomized trial

This study tests the hypothesis that addition of a protease-modulating matrix enhances the efficacy of autologous growth factors in diabetic ulcers. Fifty-one patients with chronic diabetic foot ulcers were managed as outpatients at the Democritus University Hospital of Alexandroupolis and followed up for 8 weeks. All target ulcers were ≥2.5 cm in any one dimension and had been previously treated only with moist gauze. Patients were randomly allocated in three groups of 17 patients each: Group A was treated only with the oxidized regenerated cellulose/collagen biomaterial (Promogran, Johnson & Johnson, New Brunswick, NJ), Group B was treated only with autologous growth factors delivered by Gravitational Platelet Separation System (GPS™, Biomet), and Group C was managed by a combination of both. All ulcers were digitally photographed at initiation of the study and then at change of dressings once weekly. Computerized planimetry (Texas Health Science Center ImageTool, Version 3.0) was used to assess ulcer dimensions that were analyzed for homogeneity and significance using the Statistical Package for Social Sciences, Version 13.0. Post hoc analysis revealed that there was significantly greater reduction of all three dimensions of the ulcers in Group C compared to Groups A and B (all P<.001). Although reduction of ulcer dimensions was greater in Group A than in Group B, these differences did not reach statistical significance. It is concluded that protease-modulating dressings act synergistically with autologous growth factors and enhance their efficacy in diabetic foot ulcers.

Gene therapy for tissue repair: approaches and prospects

Recent advances in molecular biology have resulted in the development of new technologies for the introduction and expression of genes in human somatic cells. This emerging field, known as gene therapy, is broadly defined as the transfer of genetic material to cells/tissues in order to achieve a therapeutic effect for inherited as well as acquired diseases. We and others are exploring the potential application of this technology to tissue repair. One primary focus has been to transfer genes encoding wound healing growth factors, a broad class of proteins which control local events in tissues such as cell proliferation, cell migration and the formation of extracellular matrix. Using several different strategies for gene transfer, wound healing growth factor genes have been introduced and expressed in cells and tissues in vitro as well as in vivo. Various experimental models of wound healing and tissue repair have been used to evaluate the efficacy of this new and exciting approach to tissue repair.

Omentum and basic fibroblast growth factor in healing of chronic gastric ulcerations in rats.

Omentum was shown to exhibit angiogenic activity, but its role in healing of chronic gastric ulcers is unknown. This study was designed to compare the effects of omentum and basic fibroblast growth factor (bFGF), a potent angiogenic factor, on healing of chronic gastric ulcers in rats. Several series of rats with gastric ulcers were used: series A with intact omentum (control), series B with omentum resected, and series C with omentum placed on the serosal side of the ulcer. Series A-C were divided into four groups treated with vehicle (I); indomethacin (II), an inhibitor of prostaglandin formation, difluoromethylornithine (DFMO) (III); an inhibitor of polyamine biosynthesis or bFGF (IV). Seven days after ulcer induction, the animals were anesthetized, the gastric blood flow (GBF) was determined by laser Doppler flowmetry (LDF), and the ulcer area was measured by planimetry. Biopsy samples of the ulcer margin were taken for determination of the number of capillaries and myofibroblasts in the granulation tissue. Attachment of omentum significantly accelerated ulcer healing, whereas omentectomy delayed this process. LDF revealed the decrease in the GBF at the ulcer margin to 45% and at the ulcer bed to 18% of the value recorded in the intact adjacent mucosa. Attachment of the omentum significantly increased the blood flow at the ulcer margin and increased the number of capillaries and myofibroblasts in the granulation tissue. Indomethacin (1 mg/kg/day) that inhibited mucosal PGE2 by about 85% delayed significantly ulcer healing without affecting the blood flow in the ulcer area.(ABSTRACT TRUNCATED AT 250 WORDS)

Basic Fibroblast Growth Factor in the Early Human Burn Wound

The role of endogenous growth factors in normal wound healing is not clear. Most of the data on growth factors in healing wounds have been obtained from the application of recombinant exogenous growth factors to animal and human wounds. We describe the immunolocalization of basic fibroblast growth factor (bFGF) in the injured dermis of skin from patients with partial and full-thickness burns. Three antibodies demonstrate an extracellular staining pattern of bFGF corresponding to areas of tissue injury that was most intense in specimens collected between 4 and 11 days post-burn injury. In contrast, bFGF staining appeared markedly decreased by Postburn Day 17 and was more consistent with uninjured tissue in a 30-day-old burn that had virtually reepithelialized. Basic FGF staining in the nonburned skin from the same patients was restricted to the dermal capillary basement membranes and the sweat glands, which is consistent with other reports of immunoreactive bFGF localization in normal adult skin. The immunohistochemical results were confirmed with Western immunoblots of the same tissue. The major band at 16.5 kDa, which is within the recognized range of the bFGF molecule's several forms, was detected in both burned and unburned tissue from the same patient. These findings support. the hypothesis that bFGF is a presynthesized mediator that is stored in either the cells or extracellular matrix, is released locally from sites of direct injury, and may be important in early wound healing. K;

Effects of Cryoprecipitate on the Healing of Chronic Wounds

Basic research has promise for clinical wound healing. Purified wound healing growth factors are not available for clinical use, but they are present in plasma and platelets and have been used in patients. Chronic wounds would seem to be good for study since the wound surface is easily measured and the patient is anxious for progress. We have done a double-blinded pilot study using autologous cryoprecipitate on chronic wounds. Three of six patients showed wound healing progress; but only one patient's wounds healed permanently. One patient developed new diabetic ulcers, and one patient failed to keratinize epithelialized skin. Cryoprecipitate may promote wound healing, but further work awaits more purified healing factors. Simple measurement of the surface area of a chronic wound may not be adequate to describe all the processes of healing.

Immunohistochemical localization of basic fibroblast growth factor in the healing stage of mouse gastric ulcer.

The aim of this study was to clarify the involvement of basic fibroblast growth factor (bFGF) in gastric ulcer healing. For this purpose, light and electron microscopic immunohistochemical studies for bFGF were performed using an experimental gastric ulcer model of mice. Ulceration was induced by the application of acetic anhydride to the serosal surface of the body of the stomach. Stomach tissues were investigated of mice at 5 days and 3 weeks respectively after treatment and also of untreated normal mice. Five days after treatment an ulcer was seen in the stomach of the experimental mice. Immunohistochemistry revealed that bFGF was localized in fibroblasts in the ulcer bed. The growth factor was distributed throughout the cytoplasm excluding organelles involved in the usual secretory system, such as rough endoplasmic reticulum, Golgi apparatus and secretory vacuoles. bFGF was also detected in the nucleus. Three weeks after treatment the surface of the ulcer lesion was completely covered by regenerated epithelium. The stomach tissues were immunohistochemically negative for bFGF both inside and outside the scar region; untreated normal stomach tissues were also negative for bFGF. These results suggest that the growth factor plays important roles in gastric ulcer healing.

Role of growth factors in cutaneous wound healing: a review.

The well-orchestrated, complex series of events resulting in the repair of cutaneous wounds are, at least in part, regulated by polypeptide growth factors. This review provides a detailed overview of the known functions, interactions, and mechanisms of action of growth factors in the context of the overall repair process in cutaneous wounds. An overview of the cellular and molecular events involved in soft tissue repair is initially presented, followed by a review of widely studied growth factors and a discussion of commonly utilized preclinical animal models. The article concludes with a summary of the preliminary results from human clinical trials evaluating the effects of growth factors in the healing of chronic skin ulcers. Throughout, the interactions among the growth factors in the wound-healing process are emphasized.

Immunohistochemical localization of growth factors in fetal wound healing

Fetal wound healing occurs rapidly, in a regenerative fashion, and without scar formation, by contrast with adult wound healing, where tissue repair results in scar formation which limits tissue function and growth. The extracellular matrix deposited in fetal wounds contains essentially the same structural components as that in the adult wound but there are distinct differences in the spatial and temporal distribution of these components. In particular the organization of collagen in the healed fetal wound is indistinguishable from the normal surrounding tissue. Rapidity of healing, lack of an inflammatory response, and an absence of neovascularization also distinguish fetal from adult wound healing. The mechanisms controlling these differing processes are undefined but growth factors may play a critical role. The distribution of growth factors in healing fetal wounds is unknown. We have studied, by immunohistochemistry, the localization of platelet-derived growth factor (PDGF), transforming growth factor beta (TGF beta), and basic fibroblast growth factor (bFGF), in fetal, neonatal, and adult mouse lip wounds. TGF beta and bFGF were present in neonatal and adult wounds, but were not detected in the fetal wounds, while PDGF was present in fetal, neonatal, and adult wounds. This pattern correlates with the known effects in vitro of these factors, the absence of an inflammatory response and neovascularization in the fetal wound, and the patterns of collagen deposition in both fetal and adult wounds. The results suggest that it may be possible to manipulate the adult wound to produce more fetal-like, scarless, wound healing.

Current Concepts in Wound Healing Growth Factor and Macrophage Interaction

Growth factors are potent wound healing promoters which accelerate incisional wound repair by distinct mechanisms. Transforming growth factor-beta (TGF-beta), a chemotactic factor, increases synthesis of extracellular matrix and stimulates granulation tissue. We demonstrated that a single topical dose of TGF-beta increased the wound breaking strength in normal models of tissue repair as well as in models of impaired wound repair, characterized by severe monocytopenia. PDGF, a chemotactic agent for inflammatory cells, with mitogenic activity, activates monocytes and stimulates collagen production, significantly increased the wound breaking strength with effects that lasted for up to 47 days. In contrast to TGF-beta, PDGF was only active in normal models of wound healing and its effects were dependent upon the presence of macrophages. PAF is a glycerophospholipid which chemotaxes and activates macrophages, but differs from growth factors in lacking mitogenic activity. A single topical dose of PAF significantly increased the wound breaking strength and promoted macrophage migration.

Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats

The healing of acetic acid-induced gastric and duodenal ulcers was examined together with biochemical indices of growth in gastric and duodenal mucosa in rats with intact or removed salivary glands after treatment with epidermal growth factor (EGF) or somatostatin, or both. After the extirpation of salivary glands, the healing rate of gastric and duodenal ulcerations was delayed and gastric content of immunoreactive EGF was reduced. This was accompanied by a significant decrease in the contents of deoxyribonucleic acid and ribonucleic acid in the gastric and duodenal mucosa. Repeated administration of EGF either subcutaneously or orally accelerated the healing of gastroduodenal ulcers in rats with intact salivary glands and completely reversed the delay in ulcer healing in sialoadenectomized animals. These effects were also accompanied by a significant increase in the growth parameters of gastric and duodenal mucosa. Administration of somatostatin, which prevented the growth-promoting action of subcutaneous EGF, resulted in a significant decrease in the EGF-stimulated healing of gastric and duodenal ulcerations in both intact and sialoadenectomized rats. Our findings suggest that cell proliferation is an important factor in healing of gastric and duodenal ulcerations and that EGF plays an important role in ulcer healing due to its mitogenic action.

Herpes simplex infections

The role of endogenous growth factors in normal wound healing is not clear. Most of the data on growth factors in healing wounds have been obtained from the application of recombinant exogenous growth factors to animal and human wounds. We describe the immunolocalization of basic fibroblast growth factor (bFGF) in the injured dermis of skin from patients with partial and full-thickness burns. Three antibodies demonstrate an extracellular staining pattern of bFGF corresponding to areas of tissue injury that was most intense in specimens collected between 4 and 11 days post-burn injury. In contrast, bFGF staining appeared markedly decreased by Postburn Day 17 and was more consistent with uninjured tissue in a 30-day-old burn that had virtually reepithelialized. Basic FGF staining in the nonburned skin from the same patients was restricted to the dermal capillary basement membranes and the sweat glands, which is consistent with other reports of immunoreactive bFGF localization in normal adult skin. The immunohistochemical results were confirmed with Western immunoblots of the same tissue. The major band at 16.5 kDa, which is within the recognized range of the bFGF molecule's several forms, was detected in both burned and unburned tissue from the same patient. These findings support. the hypothesis that bFGF is a presynthesized mediator that is stored in either the cells or extracellular matrix, is released locally from sites of direct injury, and may be important in early wound healing. K