Clinical application of growth factors and cytokines in wound healing

The clinical value of growth factor treatment of chronic wounds has yet to be determined. Beneficial effects have been reported so far only from specialized wound care centers where growth factors supplemented the results achieved with good wound care. In general optimization of current methods of external wound care, adequate metabolic and nutritional control and surgical measures should be employed before any adjuvant growth factor therapy is attempted. Current use of exogenously applied growth factors and cytokines appears to be reasonable only in the setting of controlled clinical studies according to the rules of "good clinical practice". With more knowledge on the biology of chronic wounds and progress in wound pharmacology the best application for these peptides will have to be reevaluated.     

Peptide growth factors and wound healing

An analysis of peptide growth factors and wound healing should not fail to give credit to its foundations in cancer research. Add the recent advances in peptide chemistry and molecular genetics that have permitted complete definitions and in vivo studies for the first time. The result is an enormous break-through in wound healing research. The potential for understanding and then using the growth factors to enhance healing in the aged or debilitated is incalculable.     

PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing

Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF‐β) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM‐CSF), platelet‐derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor nerosis factor‐α family. Currently, patients are treated by three growth factors: PDGF‐BB, bFGF, and GM‐CSF. Only PDGF‐BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.     

Peptide growth factors and wound healing.

Growth factors and cytokines are important signal transducers in wound microenvironments. Experimental data are accumulating rapidly which demonstrate their ability to influence populations of polymorphs and macrophages to migrate to the wound, subsequently to be replaced by synthetic cells which produce collagen and matrix; these events are controlled sequentially at cell receptor level by a variety of locally delivered (paracrine and autocrine) peptides. Preliminary results from clinical trials using recombinant human growth factors to improve cutaneous healing are encouraging. Current research aims to produce growth preparations which can be applied to a wound to accelerate healing.     

The role of growth factors in wound healing

Growth factors are mediators with essential importance for undisturbed repair process after wounding. The well coordinated concert of these substances is necessary for healing with complete restoration of function and morphology. These complex mechanisms are disturbed during secondary and delayed repair. The result is protracted healing course and inferior scar quality--either hypo- or hypertrophic. Local and systemic application of these growth factors seems to add important instruments for therapeutic use in the treatment of chronic wounds. Knowledge from experimental research is encouraging, although the exact mechanisms of synergistic action are not completely understood. However, the results from clinical use in controlled studies do not meet these expectations by far. The main reasons for this dilemma are thought to be little understanding in the complex interactions of these substances. In fact, different wound entities seem to reveal different cytokine profiles during the course of repair. Further intensive research therefore is required for the rational use of growth factors in the clinical setting.     

Age and growth factors in porcine full-thickness wound healing

It has been recognized that the rate of cutaneous wound healing declines with age, yet the molecular processes that affect this decline remain poorly understood. The purpose of this study was to compare reepithelialization and contraction rates, and growth factor profiles in full-thickness wounds in swine of various ages. Multiple full-thickness excisional wounds were created on the dorsum of 24-month-old (n=2), 4-month-old (n=2), and 2-month-old (n=2) Yucatan Minipigs. The extent of reepithelialization was shown to decrease with increasing age in a manner that was statistically significant among the 2-month-old (79%), 4-month-old (48%), and 24-month-old pigs (22%). Enzyme-linked immunosorbent assay results showed that endogenous vascular endothelial growth factor concentrations in the 2- and 4-month-old animals peaked on day 4, reaching levels of 482 pg/ml and 420 pg/ml, respectively. In the 24-month-old pigs the vascular endothelial growth factor concentration peaked later (day 6), and was present at a lower level (229 pg/ml). On day 4 the vascular endothelial growth factor levels in the older pigs reached only 120 pg/ml, representing a four-fold decrease in concentration compared to the younger pigs. A comparison of platelet-derived growth factor-BB concentrations across the age groups showed similar patterns in the 2- and 4-month-old pigs (peaks of 77 and 91 pg/ml on days 2 and 3, respectively), and levels in the 24-month-old were below the sensitivity level (31.5 pg/ml) of the assay. Transforming growth factor-beta1 levels across the age groups did not differ in a manner that was statistically significant, and all age groups peaked on day 9. Wound contraction showed no statistical differences among the age groups from days 3 to 9. On day 11, however, wound contraction in 2-month-old pigs was about 10% faster than in 24-month-old pigs (p < 0.05). These data suggest a possible new algorithm for treating wounds in aged skin, by which exogenous growth factors can be added to the wound microenvironment in doses and at times that match the growth factor profiles observed in wounds made in younger skin.     

Harnessing growth factors to influence wound healing

Cutaneous wound healing is a dynamic process with the ultimate goal of restoring skin integrity. On injury to the skin, inflammatory cells, endothelial cells, fibroblasts, and keratinocytes undergo changes in gene expression and phenotype, leading to cell proliferation, migration, and differentiation. Cytokines and growth factors play an essential role in initiating and directing the phases of wound healing. These signaling peptides are produced by a variety of cells and lead to a concerted effort to restore the skin barrier function.     

Interactions between extracellular matrix and growth factors in wound healing

Dynamic interactions between growth factors and extracellular matrix (ECM) are integral to wound healing. These interactions take several forms that may be categorized as direct or indirect. The ECM can directly bind to and release certain growth factors (e.g., heparan sulfate binding to fibroblast growth factor-2), which may serve to sequester and protect growth factors from degradation, and/or enhance their activity. Indirect interactions include binding of cells to ECM via integrins, which enables cells to respond to growth factors (e.g., integrin binding is necessary for vascular endothelial growth factor-induced angiogenesis) and can induce growth factor expression (adherence of monocytes to ECM stimulates synthesis of platelet-derived growth factor). Additionally, matrikines, or subcomponents of ECM molecules, can bind to cell surface receptors in the cytokine, chemokine, or growth factor families and stimulate cellular activities (e.g., tenascin-C and laminin bind to epidermal growth factor receptors, which enhances fibroblast migration). Growth factors such as transforming growth factor-β also regulate the ECM by increasing the production of ECM components or enhancing synthesis of matrix degrading enzymes. Thus, the interactions between growth factors and ECM are bidirectional. This review explores these interactions, discusses how they are altered in difficult to heal or chronic wounds, and briefly considers treatment implications.     

Roles of cytokines in wound healing processes]

In recent years, a number of studies have revealed the importance of cytokines and growth factors in the wound healing process. Cytokines, such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF) alpha 1 and interleukin (IL)-6, have been shown to exhibit the particular ability to stimulate keratinocyte proliferation. In addition, bFGF and TGF beta 1 not only facilitate the migration of monocytes, neutrophils, macrophages, and fibroblasts, but also play a role in the generation of granulation tissue. Cytokine modulation of the repair process in both transitory and chronic wounds remains a very important subject for investigation. In this study, the clinical application of cytokines or cytokine-promoting drugs which were combined with or without collagen matrix is discussed as well as perspectives on wound care in the future.     

Expression of growth factors in early wound healing in rat skin

Growth factors are a group of hormone-like polypeptides that have been shown to play a central role in different phases of wound healing. The expression of these growth factors in early wound healing has not been quantified, and the pattern and distribution of these growth factors in early wound healing has not been described completely. Furthermore the quantity and pattern of distribution of these growth factors have not been investigated in early wounds produced by various methods of surgical incision. Comparison of the rate of healing between the CO₂ laser wound and the scalpel wound has produced conflicting results. The present immunohistochemical study uses polyclonal antibodies specific for epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor p (TGF-β), and basic fibroblast growth factor (bFGF) to observe the pattern and distribution of these growth factors in rat skin wound and elucidate whether there are differences in the expression of these growth factors which might account for the delayed healing of the CO₂ laser wounds compared to the scalpel as has been observed by some authors. Our results indicate that EGF, TGF-β, PDGF, and bFGF are expressed and distributed in same areas of the early skin wound. The area of expression of these growth factors was associated with presence of wound inflammatory cells and wound fibroblasts. Our study found that there were no significant differences in the expression of growth factors in the majority of time points between the CO₂ laser wounds and the scalpel wounds. © 1994 wiley-Liss, Inc.     

Growth factors in wound healing

Enhancement of wound healing was limited to good surgical technique, maintenance of a clean wound with appropriate dressings, and debridement. The ability to heal wounds has been advanced through the recognition that healing in a moist environment is improved over that of a desiccated wound. Pharmacologic approaches to wound healing did not exist until the last few decades, when it was recognized that growth factors are normally present in the wound environment and that in animal models and a few clinical studies, the addition of growth factors could enhance healing. In 1998, platelet-derived growth factor was approved for clinical use. This approach is still the subject of intense investigation and clinical trials. This article analyzes current knowledge on growth factors as therapeutic agents and speculates on their future potential, with an analysis of successes and failures to date.     

三种组织内源性生长因子含量变化与创面修复的关系

目的　研究内源性生长因子含量变化对创伤修复结局的影响。方法　用放射免疫和改进的 Ｃｏｒｔａｓ 法测定３４ 例瘢痕和肉芽创面组织匀浆中 Ｅ Ｇ Ｆ、 Ｔ Ｎ Ｆ 和 Ｎ Ｏ 含量变化，并探讨这三种因子含量变化与组织修复效果的关系。结果　以上三种因子含量在瘢痕组织显著高于溃疡创面肉芽组织，其中以男性或青少年以及伤后１ ～２ 年患者的标本更为明显。结论　创面内源性生长因子含量不足或过多分别是溃疡形成与瘢痕生长的原因之一。     

三种组织内源性生长因子含量变化与创面修复的关系

目的研究内源性生长因子含量变化对创伤修复结局的影响。方法用放射免疫和改进的 Cortas 法测定34例瘢痕和肉芽创面组织匀浆中 EGF、TNF 和 NO 含量变化,并探讨这三种因子含量变化与组织修复效果的关系。结果以上三种因子含量在瘢痕组织显著高于溃疡创面肉芽组织,其中以男性或青少年以及伤后1～2年患者的标本更为明显。结论创面内源性生长因子含量不足或过多分别是溃疡形成与瘢痕生长的原因之一。     

生肌止痛膏纱条对肛周脓肿术后创面愈合及生长因子的临床疗效研究

目的 观察生肌止痛膏纱条对肛周脓肿术后创面愈合的影响,总结临床疗效。方法:将80例肛周脓肿术后患者随机均分为治疗组和对照组。治疗组予生肌止痛膏纱条换药、静滴抗生素、痔疮Ⅱ洗剂坐浴;对照组予雷夫诺尔纱条换药、静滴抗生素、痔疮Ⅱ洗剂坐浴。测量并比较两组的疼痛程度、创面减小率、创面完全愈合期、C-反应蛋白(CRP)、血管内皮生长因子(VEGF)、成纤维细胞生长因子(FGF)和血小板衍生生长因子(PDGF)含量。结果:两组肛周脓肿术后相比,治疗组疼痛轻于对照组,差异有统计学意义(P<0.05);两组创面减小率比较,术后7 d、14 d治疗组创面减小率均大于对照组,差异有统计学意义(P<0.05);两组创面完全愈合期比较,治疗组创面完全愈合期小于对照组,差异有统计学意义(P<0.05);两组CRP含量比较,术后7 d治疗组CRP含量小于对照组,差异有统计学意义(P<0.05);两组VEGF、PDGF、FGF含量比较,治疗组术后7 d、14 d、21 d创面VEGF、PDGF、FGF含量大于对照组,差异有统计学意义(P<0.05)。结论:生肌止痛膏纱条能够明显减轻肛周脓肿术后创面疼痛,促进生长因子的分泌,加快创面愈合。