Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing

Bioengineered skin substitutes for the management of burns: a systematic review.

Potential cellular and molecular causes of hypertrophic scar formation

Mechanical control of cardiac myofibroblasts.

Wound healing results from complex signaling between cells and their environment in response to injury. Fibroblasts residing within the extracellular matrix (ECM) of various connective tissues are critical for matrix synthesis and repair. Upon injury or chronic insult, these cells activate into wound-healing cells, called myofibroblasts, and repair the damaged tissue through enzyme and protein secretion. However, misregulation and persistence of myofibroblasts can lead to uncontrolled accumulation of matrix proteins, tissue stiffening, and ultimately disease. Extracellular cues are important regulators of fibroblast activation and have been implicated in their persistence. Hydrogel-based culture models have emerged as useful tools to examine fibroblast response to ECM cues presented during these complex processes. In this Mini-Review, we will provide an overview of these model systems, which are built upon naturally-derived or synthetic materials, and mimic relevant biophysical and biochemical properties of the native ECM with different levels of control. Additionally, we will discuss the application of these hydrogel-based systems for the examination of fibroblast function and fate, including adhesion, migration, and activation, as well as approaches for mimicking both static and temporal aspects of extracellular environments. Specifically, we will highlight hydrogels that have been used to investigate the effects of matrix rigidity, protein binding, and cytokine signaling on fibroblast activation. Last, we will describe future directions for the design of hydrogels to develop improved synthetic models that mimic the complex extracellular environment.

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Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease

To clarify the mechanisms underlying declines in wound contraction caused by basic fibroblast growth factor (bFGF) and the role of autologous fibroblasts in modulating wound healing, we have examined the expression of alpha-smooth muscle actin (alpha-SMA) and apoptosis in a model of wound healing using collagen sponges with and without bFGF (1 microg) and/or fibroblasts (1 x 10(6) cells/cm(2)) applied to experimentally produced full-thickness skin wounds in rats (n=10 for each group). At 7 days postoperatively, wounds filled with a fibroblast-seeded collagen sponge (fibroblast-seeded group) displayed a greater area of collagen sponge and a smaller area of fibroblasts compared with control wounds filled with collagen sponge alone (control group). Therefore, seeding of fibroblasts in the dermal substitute might retard degradation of the collagen sponge, inhibiting fibroblast infiltration into the substitute. By day 14, wounds filled with bFGF-treated collagen sponge without fibroblast seeding (bFGF group) displayed decreased alpha-SMA expression and significantly increased apoptosis compared with other wounds. Double staining revealed that apoptosis in alpha-SMA-positive fibroblastic cells was significantly increased in the bFGF group, suggesting that bFGF treatment is a potent stimulator of myofibroblast apoptosis. Furthermore, morphometric analysis demonstrated the significant decrease in the level of wound contraction and the degree of mature collagen bundle formation in the bFGF group by day 42. The bFGF group also showed increased bFGF expression in macrophages by day 28. These results suggest that bFGF administration to an artificial dermis promotes apoptosis of alpha-SMA-positive fibroblastic cells and inhibits alpha-SMA expression in the treated wound, thus reducing wound contraction.

Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of α-smooth muscle actin, leading to reduction of wound contraction

One of the specific skin lesions occurring after Bacille Calmette-Guerin (BCG) vaccination is generalized tuberculid-like eruptions, which occur rarely, but have a tendency to heal spontaneously. Their pathogenesis and relationship to "true" tuberculids are poorly understood. This report presents a case of a 6-month-old girl who developed generalized papulonecrotic tuberculid-like eruptions after BCG vaccination. The skin lesions healed spontaneously in 3 months. Culture of blood, gastric juice and reverse transcription polymerase chain reaction (RT-PCR) of papulonecrotic skin biopsies were all negative for Mycobacterium tuberculosis. Histopathology of papulonecrotic eruptions revealed marked epidermal necrosis, perivascular lymphocytic infiltrates and epidermotropic infiltration of lymphocytes showing markers of CD3(+) lymphocytes (90-95% of all infiltrating cells), CD4(+) (40-50%), CD8(+) (40-50%), and CD45RO(+) (70%). In contrast, the BCG vaccination site revealed intradermal granuloma with epithelioid cells, occasional giant cells and infiltration of lymphocytes consisting of CD3(+) (60-70%), CD4(+) (40-50%), CD8(+) (30-40%), CD45RO(+) (40%), CD79a(+) (30-40%), and CD20(+) (20-30%). Our patient did not reveal any signs indicative of tuberculosis. Papulonecrotic lesions were therefore called papulonecrotic tuberculid-like eruptions, rather than tuberculids, that occurred after BCG vaccination and appeared to derive from a hypersensitive reaction mediated by immune lymphocytic infiltration.

Papulonecrotic tuberculid‐like eruptions after Bacille Calmette‐Guerin vaccination

We have devised a bilobed skin flap for reconstruction after excision of small skin tumours. The sutured part serves as a zig-zag that leads to only slight postoperative contracture of the scar. The rotation centre of the flap is nearer to the affected area than other conventional bilobed flaps, resulting in less dog-ear deformity and distortion of tissue.

Reconstruction method with a newly-designed bilobed flap after excision of tumours of the skin.

In order to identify a means to reduce the scar formation of the skin after incision, this study examined the wound healing effect of bFGF in humans. BFGF was administered at dose of 0.1 and 1 μg per cm of sutured immediately after an operation. The drug was injected once into the dermis of the margins of wounds using a 27 G needle attached to a 1-ml syringe to the patients. The lengths of the treated wounds varied from 1.5 cm to 23 cm, and the subjects were 2 to 76 years old. Sutured wounds after excision of skin tumors from the face, trunk and limbs and the sutured wounds such as those at the donor sites of full thickness skin grafts were treated with low dose bFGF injections. Postoperative administration of bFGF, inhibited scaring and accelerated healing without any serious side effects. Although double–blind studies are needed, we expect that so-called scar-less surgery may be possible by establishing of more sophisticated methods for administering bFGF and its combination with other drugs and/or gene therapy in the future.

Akihiro Tominaga

Papers

Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of α-smooth muscle actin, leading to reduction of wound contraction

Papulonecrotic tuberculid‐like eruptions after Bacille Calmette‐Guerin vaccination

Reconstruction method with a newly-designed bilobed flap after excision of tumours of the skin.

Modification of Wound Healing Process Using Basic Fibroblast Growth Factor

A case of Stewart-Treves syndrome following treatment for breast cancer