Holger G. Gassner

Wound healing after radiation therapy: Review of the literature

Radiation therapy is an established modality in the treatment of head and neck cancer patients. Compromised wound healing in irradiated tissues is a common and challenging clinical problem. The pathophysiology and underlying cellular mechanisms including the complex interaction of cytokines and growth factors are still not understood completely. In this review, the current state of research regarding the pathomechanisms of compromised wound healing in irradiated tissues is presented. Current and possible future treatment strategies are critically reviewed.

CSF rhinorrhea: 95 consecutive surgical cases with long term follow-up at the Mayo Clinic.

A persistent cerebrospinal fluid (CSF) leak is potentially lethal, and surgical treatment is often required. CSF leak repair is an infrequently performed procedure, and only limited information is available on the long term success of the surgical techniques that are used. This retrospective chart review includes 95 patients who underwent various types of repair surgery for CSF rhinorrhea at the Mayo Clinic. The purpose of this study was to extract factors such as the choice of sealing material, etiology, location of defect(s), surgical approach, and previous procedures, and to analyze their association with the long term success and failure of surgical repair. The mean time interval in this study between unsuccessful surgery and recurrence was 50.8 months, and the mean follow-up 109 months. Among the various approaches, defects repaired endonasally had the lowest recurrence rate. Local nasal mucosa advancement flaps failed more frequently (83.3% failure) than other types of graft material (p = 0.023). These failures took place in a delayed fashion (mean interval until failure: 80 months). Local osteo-mucoperiosteal or chondro-mucoperichondrial flaps (22.2% recurrence rate) and free graft material (15.6% recurrence rate) had the best outcome. The use of fibrin glue to fixate free grafts did not improve the result in this series. Transcranial procedures were associated with a higher complication rate than extracranial procedures (12.9% versus 3.2%). Overall, successful repair was achieved in 91.6% of the patients. We discourage the use of mucosa advancement flaps and advocate free grafts or pedicled osteomucoperiosteal or chondro-mucoperichondrial flaps as sealing material of choice in the majority of cases. The occurrence of delayed failure has to be considered when evaluating reports of CSF rhinorrhea after surgical repair.

Treatment of facial wounds with botulinum toxin A improves cosmetic outcome in primates.

Surgeons have constantly sought to achieve the most aesthetic scar. A major factor determining the final cosmetic appearance of a cutaneous scar is the tension acting on the wound edges during the healing phase. Since Theodor Kocher pioneered the alignment of skin incisions with Langer’s lines in 1892, surgical techniques that attempt to overcome closing tension have become standard. Yet, no treatment has been available to minimize underlying muscle contractions, which are the major cause of this tension. Botulinum toxin A is a potent drug that produces temporary muscular paralysis when injected locally. It has proven to be safe and effective in the treatment of a variety of disorders, including hyperkinetic facial lines. The objective of this randomized, double-blind, placebo-controlled primate study was to investigate the efficacy of a single injection of botulinum toxin A to improve the cosmetic appearance of cutaneous scars. Symmetric pairs of standardized excisions were performed on either side of the forehead of six primates. The half foreheads were randomized to the botulinum toxin A treatment side versus the placebo injection side. A panel of three blinded facial surgeons assessed the cosmetic appearance of the mature scars 3 months postoperatively. The wounds that had been immobilized with botulinum toxin A were rated as significantly better in appearance than the control wounds (p < 0.01). Histologic examination confirmed that all scars were mature. Blinded, randomized, placebo-controlled human clinical trials are presently under way at the Mayo Clinic.

Botulinum toxin to minimize facial scarring.

Botulinum toxin injection has been used for a variety of indications in humans, including blepharospasm and hyperfunctional facial lines. This article describes a novel formulation of botulinum toxin, which supplies immediate feedback to the injecting physician. Additionally, recent findings are described that indicate the immediate injection of botulinum toxin into the muscles underlying a wound can improve the cosmetic outcome of the facial cutaneous scar. Future applications of these findings are discussed.

Chemoimmobilization: improving predictability in the treatment of facial scars.

A major goal of incision closure and traumatic laceration repair is to minimize scarring. An important factor determining the final cosmetic appearance of cutaneous scars is tension acting on wound edges during healing.1–4 The principle of chemoimmobilization to reduce tension and improve healing was investigated in a previous study. Injection of botulinum toxin into the musculature underlying cutaneous wounds resulted in immobilization of the healing wounds and significantly better cosmetic appearance than found in nonimmobilized control wounds in primates.5 This research led to the use of botulinum toxin to treat facial incisions and lacerations in humans.6 Shortcomings of botulinum toxins include the delayed onset of action and lack of immediate feedback on the treatment result. The need to immobilize cutaneous wounds in a more controlled and predictable fashion led to further research. In a recent study, we demonstrated that immediate paralysis of musculature injected with botulinum toxin type A can be achieved with a new formulation, which enhances the predictability of the treatment effect.7

Effects of botulinum toxin A on patient‐specific keloid fibroblasts in vitro

To test whether therapeutic effects of botulinum toxin A on patient‐ specific keloid tissue can be reproduced on the cellular level. Specifically, effects on cell proliferation and expression of growth factors and cytokines relevant for wound healing were to be tested.

Botulinum toxin-induced immobilization of lower facial wounds.

A n increasing body of evidence suggests that botulinum toxin–induced immobilization of facial wounds results in enhanced wound healing. Most of these data were acquired on forehead wounds. The forehead is a particularly favorable area to treat because of its low associated risk of inducing temporary functional deficits. The injection techniques applied in wound healing are derived from the widespread experience with cosmetic facial injections in the forehead. In recent years, the indications for botulinum toxin (Botox; Allergan, Irvine, California) treatment of facial lines have been extended beyond the forehead. Analogous to the progression of cosmetic indications, extension of Botox treatment for wound healing to the lower face would seem to be intuitive. Important functions of the perioral musculature include facial expression, oral sphincter, and articulation. These functions are easily compromised with injection of Botox. Transient functional deficits may therefore be anticipated with immobilization of perioral wounds. The perceived risk of inducing such functional deficits may explain the paucity of reports in the literature on perioral wound immobilization. After extensive discussion of all aspects of chemoimmobilization of the lower facial wounds, including the off-label use of Botox and the expected transient adverse effects, we have treated selected patients with perioral wounds. The following cases illustrate important aspects of therapy and clinical follow-up.

Effects of Botulinum Toxin A on Cytokine Synthesis in a Cell Culture Model of Cutaneous Scarring

OBJECTIVE To evaluate possible botulinum toxin A effects in a cell culture model. METHODS In a cell culture model with dermal fibroblasts and microvascular endothelial cells, possible botulinum toxin A effects were evaluated. Cell proliferation and cytokine expression were analyzed using viability assays and enzyme-linked immunosorbent assay techniques. RESULTS Neither cell proliferation nor cytokines and growth factors (interleukin 6, monocyte chemoattractant protein 2, fibroblast growth factor, macrophage colony-stimulating factor, and vascular endothelial growth factor) were affected by botulinum toxin A incubation. CONCLUSIONS The present data do not add evidence to suggest a significant therapeutic role of botulinum toxin A injections for cutaneous wound healing beyond chemoimmobilization. Further studies that include patient-specific cells of hypertrophic scars are required to better understand what role botulinum toxin A can play in the treatment of mature scar tissue.

Preformed titanium cranioplasty after resection of skull base meningiomas – A technical note

INTRODUCTION Meningiomas of the fronto-basal skull are difficult to manage as the treatment usually includes extensive resection of the lesion, consecutive reconstruction of the meninges and of the skull. Especially after removal of spheno-orbital and sphenoid-wing meningiomas, the cosmetic result is of utmost importance. In this technical note, we present our institutional approach in the treatment of skull base meningiomas, focussing on the reconstruction of the neurocranium with individually preformed titanium cranioplasty (CRANIOTOP(®), CL Instruments, Germany). CASE REPORT Two female patients (40 years, 64 years) are presented. Both patients presented with skull base lesions suggestive of meningiomas. The preoperative thin-sliced CT scan was processed to generate a 3D-model of the skull. On it, the resection was mapped and following a simulated resection, the cranioplasty was manufactured. Intra-operatively, the titanium plate served as a template for the skull resection and was implanted after microsurgical tumour removal, consecutively. The cosmetic result was excellent. Immediate postoperative CT scan revealed accurate fitting and complete tumour removal. Control Magnetic Resonance Imaging (MRI) within 12 weeks was possible without any artifacts. DISCUSSION The comprehensive approach described indicates only one surgical procedure for tumour removal and for reconstruction of the skull. The titanium plate served as an exact template for complete resection of the osseous parts of the tumour. Cosmetic outcome was excellent and control MRI was possible post operatively. CONCLUSION CRANIOTOP(®) cranioplasty is a safe and practical tool for reconstruction of the skull after meningioma surgery.

A Co-Culture Model of Fibroblasts and Adipose Tissue-Derived Stem Cells Reveals New Insights into Impaired Wound Healing After Radiotherapy

External radiation seems to be associated with increased amounts of cytokines and other cellular modulators. Impaired microcirculation and fibrosis are examples of typical long term damage caused by radiotherapy. Adipose tissue-derived stem cells (ASC) are discussed to enhance wound healing, but their role in wounds due to radiotherapy is poorly understood. Normal human fibroblasts (NHF) and ASCs were co-cultured and external radiation with doses from 2–12 Gray (Gy) was delivered. Cell proliferation and mRNA levels of matrix metalloproteinases (MMP1, MMP2 and MMP13) were determined 48 h after irradiation of the co-cultures by qPCR. Additionally, tissue inhibitors of matrix metalloproteinases (TIMP1, TIMP2) were determined by enzyme-linked immunosorbent assay (ELISA). There was a reduction of cell proliferation after external radiation in mono-cultures of NHFs and ASCs compared to controls without irradiation. The co-culture of ASCs and NHFs showed reduced impairment of cell proliferation after external radiation. Gene expression of MMP1 and MMP13 was reduced after external irradiation in NHF. MMP2 expression of irradiated NHFs was increased. In the co-culture setting, MMP1 and MMP2 gene expression levels were upregulated. TIMP1 and TIMP2 protein expression was increased after irradiation in NHFs and their co-cultures with ASCs. ASCs seem to stimulate cell proliferation of NHFs and modulate relevant soluble mediators as well as proteinases after external radiation.