Frank B. Niessen

On the nature of hypertrophic scars and keloids: A review

On the Nature of Hypertrophic Scars and Keloids: A Review Frank Niessen;Paul Spauwen;Joost Schalkwijk;Moshe Kon; Plastic and Reconstructive Surgery

Macrophages in skin injury and repair

After recruitment to the wound bed, monocytes differentiate into macrophages. Macrophages play a central role in all stages of wound healing and orchestrate the wound healing process. Their functional phenotype is dependent on the wound microenvironment, which changes during healing, hereby altering macrophage phenotype. During the early and short inflammatory phase macrophages exert pro-inflammatory functions like antigen-presenting, phagocytosis and the production of inflammatory cytokines and growth factors that facilitate the wound healing process. As such, the phenotype of wound macrophages in this phase is probably the classically activated or the so-called M1 phenotype. During the proliferative phase, macrophages stimulate proliferation of connective, endothelial and epithelial tissue directly and indirectly. Especially fibroblasts, keratinocytes and endothelial cells are stimulated by macrophages during this phase to induce and complete ECM formation, reepithelialization and neovascularization. Subsequently, macrophages can change the composition of the ECM both during angiogenesis and in the remodelling phase by release of degrading enzymes and by synthesizing ECM molecules. This suggests an important role for alternatively activated macrophages in this phase of wound healing. Pathological functioning of macrophages in the wound healing process can result in derailed wound healing, like the formation of ulcers, chronic wounds, hypertrophic scars and keloids. However, the exact role of macrophages in these processes is still incompletely understood. For treating wound repair disorders more should be elucidated on the role of macrophages in these conditions, especially their functional phenotype, to find more therapeutic opportunities. This review summarizes macrophage function in skin injury repair, thereby providing more insight in macrophage function in wound healing and possible interventions in this process.

Potential cellular and molecular causes of hypertrophic scar formation

A scar is an expected result of wound healing. However, in some individuals, and particularly in burn victims, the wound healing processes may lead to a fibrotic hypertrophic scar, which is raised, red, inflexible and responsible for serious functional and cosmetic problems. It seems that a wide array of subsequent processes are involved in hypertrophic scar formation, like an affected haemostasis, exaggerated inflammation, prolonged reepithelialization, overabundant extracellular matrix production, augmented neovascularization, atypical extracellular matrix remodeling and reduced apoptosis. Platelets, macrophages, T-lymphocytes, mast cells, Langerhans cells and keratinocytes are directly and indirectly involved in the activation of fibroblasts, which in turn produce excess extracellular matrix. Following the chronology of normal wound healing, we unravel, clarify and reorganize the complex molecular and cellular key processes that may be responsible for hypertrophic scars. It remains unclear whether these processes are a cause or a consequence of unusual scar tissue formation, but raising evidence exists that immunological responses early following wounding play an important role. Therefore, when developing preventive treatment modalities, one should aim to put the early affected wound healing processes back on track as quickly as possible.

Prevention and curative management of hypertrophic scar formation

Although hypertrophic scarring commonly occurs following burns, many aspects such as incidence of and optimal treatment for scar hypertrophy remain unclear. This review will focus on hypertrophic scar formation after burn in particular, exploring multiple treatment options and describing their properties as well as effectiveness. To evaluate treatment efficacy and scar development, clinical scar assessment is of eminent importance. Furthermore, recommendations regarding the classification of hypertrophy in the daily practice and in clinical trials are implemented.

Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: An objective histopathological analysis

Normotrophic, hypertrophic, and keloidal scars are different types of scar formation, which all need a different approach in treatment. Therefore, it is important to differentiate between these types of scar, not only clinically but also histopathologically. Differences were explored for collagen orientation and bundle thickness in 25 normal skin, 57 normotrophic scar, 56 hypertrophic scar, and 56 keloid biopsies, which were selected on clinical diagnosis. Image analysis was performed by fast fourier transformation. The calculated collagen orientation index ranged from 0 (random orientation) to 1 (parallel orientation). The bundle distance was calculated by the average distance between the centers of the collagen bundles. The results showed that compared with all three types of scars, the collagen orientation index was significantly lower in normal skin, which indicates that scars are organized in a more parallel manner. No differences were found between the different scars. Secondly, compared with normal skin, normotrophic scar, and hypertrophic scar, the bundle distance was significantly larger in keloidal scar, which suggests that thicker collagen bundles are present in keloidal scar. This first extensive histological study showed objective differences between normal skin, normotrophic, hypertrophic, and keloidal scar.

Freshly isolated stromal cells from the infrapatellar fat pad are suitable for a one-step surgical procedure to regenerate cartilage tissue

BACKGROUND AIMS Stem cell therapies are being evaluated as promising alternatives for cartilage regeneration. We investigated whether stromal vascular fraction cells (SVF) from the infrapatellar (Hoffa) fat pad are suitable for a one-step surgical procedure to treat focal cartilage defects. METHODS SVF was harvested from patients undergoing knee arthroplasty (n = 53). Colony-forming unit (CFU) assays, growth kinetics and surface marker profiles were determined, and the chondrogenic differentiation capacity of freshly isolated SVF was assessed after seeding in three-dimensional poly (L-lactic-co-epsilon-caprolactone) scaffolds. RESULTS SVF yield per fat pad varied between 0.55 and 16 x 10(6) cells. CFU frequency and population doubling time were 2.6 +/- 0.6% and +/-2 days, respectively. Surface marker profiles matched those of subcutaneous-derived adipose-derived stem cells (ASC). CFU from Hoffa SVF showed differentiation toward osteogenic and adipogenic lineages. Cartilage differentiation was confirmed by up-regulation of the cartilage genes sox9, aggrecan, collagen type II and cartilage oligomeric matrix protein (COMP), collagen II immunostaining, Alcian Blue staining and glycosaminoglycan production. Compared with passaged cells, SVF showed at least similar chondrogenic potential. CONCLUSIONS This study demonstrates that SVF cells from the infrapatellar fat pad are suitable for future application in a one-step surgical procedure to regenerate cartilage tissue. SVF shows similar favorable characteristics as cultured ASC, and chondrogenic differentiation even appears to be slightly better. However, because of variable harvesting volumes and yields, SVF from the infrapatellar fat pad might only be applicable for treatment of small focal cartilage defects, whereas for larger osteoarthritic defects subcutaneous adipose tissue depot would be preferable.

Detrimental dermal wound healing: What can we learn from the oral mucosa?

Wounds in adults are frequently accompanied by scar formation. This scar can become fibrotic due to an imbalance between extracellular matrix (ECM) synthesis and ECM degradation. Oral mucosal wounds, however, heal in an accelerated fashion, displaying minimal scar formation. The exact mechanisms of scarless oral healing are yet to be revealed. This review highlights possible mechanisms involved in the difference between scar‐forming dermal vs. scarless oral mucosal wound healing. Differences were found in expression of ECM components, such as procollagen I and tenascin‐C. Oral wounds contained fewer immune mediators, blood vessels, and profibrotic mediators but had more bone marrow–derived cells, a higher reepithelialization rate, and faster proliferation of fibroblasts compared with dermal wounds. These results form a basis for further research that should be focused on the relations among ECM, immune cells, growth factors, and fibroblast phenotypes, as understanding scarless oral mucosal healing may ultimately lead to novel therapeutic strategies to prevent fibrotic scars.

The role of suture material in hypertrophic scar formation : Monocryl vs. vicryl-rapide

The development of hypertrophic scars and keloids is an unsolved problem in the process of wound healing. There are indications that inflammation plays an important role in this process, but its exact mechanism remains unclear. In this study the amount of inflammation and the development of hypertrophic scars and keloids was investigated in inframammary skin incisions sutured with synthetic absorbable suture materials: a monofilamentous suture (Monocryl) compared with a multifilamentous suture (Vicryl-rapide). In 81 breast reduction patients Monocryl (N = 28) has proved to give significantly smaller, less reactive scars with a lower tendency toward hypertrophic scar formation compared with Vicryl-rapide (N = 53).

Human hypertrophic and keloid scar models: principles, limitations and future challenges from a tissue engineering perspective.

Most cutaneous wounds heal with scar formation. Ideally, an inconspicuous normotrophic scar is formed, but an abnormal scar (hypertrophic scar or keloid) can also develop. A major challenge to scientists and physicians is to prevent adverse scar formation after severe trauma (e.g. burn injury) and understand why some individuals will form adverse scars even after relatively minor injury. Currently, many different models exist to study scar formation, ranging from simple monolayer cell culture to 3D tissue‐engineered models even to humanized mouse models. Currently, these high‐/medium‐throughput test models avoid the main questions referring to why an adverse scar forms instead of a normotrophic scar and what causes a hypertrophic scar to form rather than a keloid scar and also, how is the genetic predisposition of the individual and the immune system involved. This information is essential if we are to identify new drug targets and develop optimal strategies in the future to prevent adverse scar formation. This viewpoint review summarizes the progress on in vitro and animal scar models, stresses the limitations in the current models and identifies the future challenges if scar‐free healing is to be achieved in the future.

Time course of the angiogenic response during normotrophic and hypertrophic scar formation in humans

Previous research suggests that in hypertrophic scars (HSs), an excess of microvessels is present compared with normotrophic scars (NSs). The aim of our study was to quantify vascular densities in HSs and normotrophic scars and to provide an insight into the kinetics of changes in the expression of angiogenic factors in time during wound healing and HS formation. Human presternal wound healing after cardiothoracic surgery through a sternotomy incision was investigated in a standardized manner. Skin biopsies were collected at consecutive time points, i.e., during surgery and 2, 4, 6, 12, and 52 weeks postoperatively. The expression levels of angiopoietin‐1, angiopoietin‐2, Tie‐2, vascular endothelial growth factor, and urokinase‐type plasminogen activator were measured by real‐time reverse transcription‐polymerase chain reaction. Quantification of angiogenesis and cellular localization of the proteins of interest were based on immunohistochemical analysis. Microvessel densities were higher in the HSs compared with the normotrophic scars 12 weeks (p=0.017) and 52 weeks (p=0.030) postoperatively. Angiopoietin‐1 expression was lower in the hypertrophic group (p<0.001), which, together with a nonsignificant increase of angiopoietin‐2 expression, represented a considerable decrease in the angiopoietin‐1/angiopoietin‐2 ratio in the hypertrophic group 4 weeks (p=0.053), 12 weeks (p<0.001), and 52 weeks (p<0.001) postoperatively. The expression of urokinase‐type plasminogen activator was up‐regulated during HS formation (p=0.008). Vascular endothelial growth factor expression was not significantly different when comparing both groups. In summary, the differential expression of angiopoietin‐1, angiopoietin‐2, and urokinase‐type plasminogen activator in time is associated with an increased vascular density in HSs compared with normotrophic scars.