Hildegunde Piza-Katzer

Hypertrophic scars and keloids--a review of their pathophysiology, risk factors, and therapeutic management

BACKGROUND Hypertrophic scars and keloids result from an abnormal fibrous wound healing process in which tissue repair and regeneration‐regulating mechanism control is lost. These abnormal fibrous growths present a major therapeutic dilemma and challenge to the plastic surgeon because they are disfiguring and frequently recur. OBJECTIVE To provide updated clinical and experimental information on hypertrophic scars and keloids so that physicians can better understand and properly treat such lesions. METHODS A Medline literature search was performed for relevant publications and for diverse strategies for management of hypertrophic scars and keloids. CONCLUSION The growing understanding of the molecular processes of normal and abnormal wound healing is promising for discovery of novel approaches for the management of hypertrophic scars and keloids. Although optimal treatment of these lesions remains undefined, successful healing can be achieved only with combined multidisciplinary therapeutic regimens. The authors have indicated no significant interest with commercial supporters.

Surgery for Foreign Body Reactions due to Injectable Fillers

Background: An increasing number of soft tissue fillers have been introduced to the beauty market and these filler substances are widely used as non-toxic, non-immunogenic and relatively harmless injectable alternatives to surgical rejuvenation. Generally, facial fillers are injectable – or surgically insertable – products that are used to fill up the volume loss in the aging face. Depending on bioavailability, chemical composition and degradation, fillers can be classified as temporary or permanent, organic or inorganic and autologous or heterologous. Objective: A plethora of new products has swamped the beauty market since face rejuvenation has become socially acceptable as well as affordable to a wider population, but adverse reactions cannot be excluded. We present 4 patients with complications after injection of facial fillers [including Artecoll®(polymethylmethacrylate microspheres), Restylane® (hyaluronic acid), DermaLive® (hyaluronic acid plus acrylic hydrogel particles) and Newfill® (polylactic acid)] and surgical correction. Results: Surgical intervention led to good aesthetic and functional results after multiple unsuccessful conservative therapies. Conclusion: We recommend that only physicians familiar with the injection techniques and the biological and chemical characteristics of the various injectable products should perform such interventions. Especially permanent fillers should be used with utmost reticence in cosmetic surgery and we would recommend their application only in reconstructive procedures. Additionally, documentation and reporting of all adverse effects must be mandatory.

Histomorphologic and Volumetric Analysis of Implanted Autologous Preadipocyte Cultures Suspended in Fibrin Glue: A Potential New Source for Tissue Augmentation

Abstract. Previous efforts to use adipocyte transplants for tissue augmentation have been limited by high and unpredictable resorption rates. Preadipocytes are precursor cells that are capable of replication and differentiation into mature adipocytes. Furthermore, they are more resilient to ischemia, making them a desirable transplant media. Utilizing fibrin glue as a transport vehicle and a prefabricated intramuscular capsule pouch as the recipient site, we have demonstrated the successful transplantation of cultured preadipocytes without the previously presented resorption sequelae. Histological analysis at 2 weeks has demonstrated establishment of vascular supply and the complete resorption of fibrin glue. Most importantly, using planimetric analysis, volume retention has been demonstrated in implanted areas up to 1 year following implantation. Finally, BrdU labeling has been utilized to demonstrate the lack of increased and uncontrolled replication rate, an index of potentially tumorigenic tissue. In conclusion, we have demonstrated a potentially new and safe source of tissue augmentation in the rat model.

First forearm transplantation : Outcome at 3 years

We here report on the surgical procedure, postoperative course and functional results at 3 years following the first bilateral forearm transplantation. A 41‐year‐old male underwent bilateral forearm transplantation on February 17, 2003. After ATG induction therapy, tacrolimus, prednisone and MMF were given for maintenance immunosuppression. At 16 months, MMF was switched to everolimus. Hand function, histology, immunohistochemistry, radiomorphology, motor and nerve conduction and somatosensory‐evoked potentials were investigated at frequent intervals. A total of six rejection episodes required treatment with either steroids, basiliximab, ATG, alemtuzumab or tacrolimus dose augmentation. At 3 years, the patient is free of clinical signs of rejection despite a persisting minimal perivascular lymphocytic dermal infiltrate. No signs of myointimal proliferation in graft vessels were seen. Motor function continuously improved, resulting in satisfactory hand function. Intrinsic hand muscle function was first observed at 16 months and continues to improve. Although discrimination of hot and cold recovered, overall sensitivity remains poor. The patient is satisfied with the outcome. Bilateral forearm transplantation represents a novel therapeutic option after loss of forearms.

Successful transplantation of three tissue-engineered cell types using capsule induction technique and fibrin glue as a delivery vehicle.

Recent advances in cell biology and tissue engineering have used various delivery vehicles for transplanting varying cell cultures with limited success. These techniques are frequently complicated by tissue necrosis, infection, and resorption. The purpose of this study was to investigate whether urothelium cells, tracheal epithelial cells, and preadipocytes cultured in vitro could be successfully transplanted onto a prefabricated capsule surface by using fibrin glue as a delivery vehicle, with the ultimate goal for use in reconstruction. In the first step of the animal study, tissue specimens (bladder urothelium, tracheal epithelial cells, epididymal fat pad) were harvested for in vitro cell culturing, and a silicone block was implanted subcutaneously or within the anterior rectus sheath to induce capsule formation. After 6 to 10 days, when primary cultures were confluent, the animals were re-anesthetized, the newly formed capsule pouches were incised, and the suspensions of cultured urothelia cells (n = 40), tracheal epithelial cells (n = 32), and preadipocytes (n = 40) were implanted onto the capsule surface in two groups, one using standard culture medium as a delivery vehicle and the second using fibrin glue. Histologic sections were taken, and different histomorphologic studies were performed according to tissue type. Consistently in all animals, a highly vascularized capsule was induced by the silicon material. In all animals in which the authors used fibrin glue as a delivery vehicle, they could demonstrate a successful reimplantation of cultured urothelium cells, tracheal epithelial cells, or preadipocytes. Their animal studies showed that capsule induction in combination with fibrin glue as a delivery vehicle is a successful model for transplantation of different in vivo cultured tissue types.

Status 5 Years after Bilateral Hand Transplantation

Graft survival and function early after hand transplantation is good. It remains unknown, however, whether long‐term survival is limited by chronic rejection. We here describe the clinical course and the status 5 years after bilateral hand transplantation with emphasis on immunosuppression (IS), function, morphology and graft vascular changes.

The Innsbruck hand transplant program: update at 8 years after the first transplant.

We herein provide an update on two bilateral hand and one bilateral forearm transplants with emphasis on immunosuppression (IS), function, morphology, and graft vascular changes at 8 years and 2 years after bilateral hand and 5 years after bilateral forearm transplantation. Between March 2000 and May 2006, three patients underwent bilateral hand or forearm transplantation at our institution. Following induction therapy with antithymocyte globulin (ATG) (n = 2) or alemtuzumab (n = 1), tacrolimus, prednisolone +/- mycophenolate mofetil (MMF) were given for maintenance IS. Later, tacrolimus (n = 1) or MMF (n = 1) was replaced by sirolimus/everolimus for long-term IS. Clinical follow-ups with evaluation of hand function, skin biopsies, X-ray, ultrasound, angiography, computed tomography angiography, electrophysiological studies, and somatosensory evoked potentials were performed at regular intervals. Three, six, and three rejection episodes were successfully treated with bolused steroids, anti-CD25 or anti-CD52 antibodies. Subsequently, skin histology remained normal without any evidence of chronic rejection. Hand function continuously improved during the first 3 years and since then remained stable with minor improvements. Investigation of hand arteries revealed no signs of occlusion or stenosis. Motor and intrinsic hand muscle function continues to improve in all patients. Protective sensation was observed in all patients; however, discriminative sensation was only accomplished after hand but not forearm transplantation. No life-threatening adverse events occurred. Despite immunologic challenging postoperative courses, patients are now free of rejection with moderate levels of IS and good functional results. No signs indicating chronic rejection have been encountered.

Small free vascularized iliac crest bone grafts in reconstruction of the scaphoid bone: a retrospective study in 60 cases.

Carpal instability may result in progressive degenerative arthritis of the wrist. The surgical goal of the reconstruction of scaphoid nonunion is to achieve bone union and to restore the scaphoid. Many procedures are described to treat scaphoid nonunion for different indications. This retrospective study reports on the anatomical fundamentals, the operative procedure, and the results of 60 patients (21 with recalcitrant scaphoid nonunion that lasted longer than 4 years, 26 with an avascular pole fragment, and 13 with scaphoid nonunion after previous surgery) who were treated by a small free vascularized iliac crest bone graft. All 60 patients have routinely been followed up clinically and with magnetic resonance imaging. Union was achieved in 91.7 percent by improvement of stability and the compromised vascularity of the scaphoid. The bone flap loss rate and persisting nonunion was 8.3 percent, leading to progressive arthritis and carpal collapse. Complaints concerning discomforts caused by the scar were heard from 40.1 percent of the patients, and 31.7 percent complained of discomforts caused by the bony deformity. Bone deformations on the donor site were detected radiologically in 63.3 percent of the patients. In 31.7 percent, an impairment of the lateral femoral cutaneous nerve was noted. Reconstruction of the scaphoid by means of implantation of a vascularized iliac bone graft proved efficient to treat avascular recalcitrant scaphoid nonunion and pseudarthrosis with avascular proximal pole fragments. (Plast. Reconstr. Surg. 108: 664, 2001.)

PORCN mutations in focal dermal hypoplasia: coping with lethality.

The X‐linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X‐chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi‐Hünermann‐Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X‐chromosomal mutations by extreme skewing of X‐chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1α- and basic FGF-dependent pathway in muscle cells

Expression of angiogenic cytokines like vascular endothelial growth factor is enhanced by hypoxia. We tested the hypothesis that decreased oxygen levels up‐regulate the angiogenic factor sec‐retoneurin. In vivo, muscle cells of mouse ischemic hind limbs showed increased secretoneurin expression, and inhibition of secretoneurin by a neutralizing antibody impaired the angiogenic response in this ischemia model. In a mouse soft tissue model of hypoxia, secretoneurin was increased in subcutaneous muscle fibers. In vitro, secretoneurin mRNA and protein were up‐regulated in L6 myoblast cells after exposure to low oxygen levels. The hypoxia‐depen‐dent regulation of secretoneurin was tissue specific and was not observed in endothelial cells, vascular smooth muscle cells, or AtT20 pituitary tumor cells. The hypoxia‐dependent induction of secretoneurin in L6 myoblasts is regulated by hypoxia‐inducible factor‐la, since inhibition of this factor using si‐RNA inhibited up‐regulation of secretoneurin. Induction of secretoneurin by hypoxia was dependent on basic fibroblast growth factor in vivo and in vitro, and inhibition of this regulation by heparinase suggests an involvement of low‐affinity basic fibroblast growth factor binding sites. In summary, our data show that the angiogenic cytokine secretoneurin is up‐regulated by hypoxia in muscle cells by hypoxia‐inducible factor‐1α‐ and basic fibroblast growth factor‐dependent mechanisms.—Egger, M., Schgoer, W., Beer, A. G. E., Jeschke, J., Leierer, J., Theurl, M., Frauscher, S., Tepper, O. M., Niederwanger, A., Ritsch, A., Kearney, M., Wanschitz, J., Gurtner, G. C., Fischer‐Colbrie, R., Weiss, G., Piza‐Katzer, H., Losordo, D. W., Patsch, J. R., Schratzberger, P., Kirchmair, R. Hypoxia up‐regulates the angiogenic cytokine secretoneurin via an HIF‐1α‐ and basic FGF‐dependent pathway in muscle cells. FASEB J. 21, 2906–2917 (2007)