Thrombomodulin overexpression to limit neointima formation.

BACKGROUND-These studies were initiated to confirm that high-level thrombomodulin overexpression is sufficient to limit neointima formation after mechanical overdilation injury. METHODS AND RESULTS-An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand White rabbit common femoral arteries were treated with buffer, viral control, or Adv/RSV-THM and subjected to mechanical overdilation injury. The treated vessels (n=4 per treatment) were harvested after 28 days and evaluated to determine intima-to-media (I/M) ratios. Additional experiments were performed to determine early (7-day) changes in extracellular elastin and collagen content; local macrophage, T-cell, and neutrophil infiltration; and local thrombus formation as potential contributors to the observed impact on 28-day neointima formation. The construct significantly decreased neointima formation after mechanical dilation injury in this model. By histological analysis, buffer controls exhibited mean I/M ratios of 0.76+/-0.06%, whereas viral controls reached 0.77+/-0.08%; in contrast, Adv/RSV-THM reduced I/M ratios to 0.47+/-0.06%. Local inflammatory infiltrate decreased in the Adv/RSV-THM group relative to controls, whereas matrix remained relatively preserved. Rates of early thrombus formation also decreased in Adv/RSV-THM animals. CONCLUSIONS-This construct thus offers a viable technique for promoting a locally neointima-resistant small-caliber artery via decreased thrombus bulk, normal matrix preservation, and decreased local inflammation without the inflammatory damage that has limited many other adenoviral applications.

Hereditary neuropathy with liability to pressure palsies is not a major cause of idiopathic carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome is a debilitating neuropathy affecting millions of individuals. Although there are published reports of familial associations of carpal tunnel syndrome, the molecular mechanisms are unknown. OBJECTIVE: To determine the prevalence and potential role of the chromosome 17 microdeletion associated with hereditary neuropathy with liability to pressure palsies in patients diagnosed as having carpal tunnel syndrome. DESIGN: Prospective study. PATIENTS AND METHODS: Since hereditary neuropathy with liability to pressure palsies may present as carpal tunnel syndrome, we evaluated 50 patients with idiopathic carpal tunnel syndrome for hereditary neuropathy with liability to pressure palsies. RESULTS: No hereditary neuropathy with liability to pressure palsies deletions were detected. CONCLUSION: Molecular genetic testing for hereditary neuropathy with liability to pressure palsies in patients with idiopathic carpal tunnel syndrome is of limited value.

Cardiac surgery in patients with end-stage renal disease.

In a retrospective study we analyzed the clinical features of 85 patients with end-stage renal disease who underwent cardiac operation. Seventy-eight patients were from reports in the literature, and 7 were from our experience. The cardiac procedures were primarily valve replacements and aortocoronary bypass (ACB) operations. The indication for valve replacement was most commonly infective endocarditis (73%), affecting most frequently the aortic valve (68%). The most common organism was Staphylococcus aureus, and there was a recent episode of angioaccess site infection in at least 17.5% of patients with documented endocarditis. The 30-day mortality was 57% for patients undergoing emergency valve replacement and only 3% for similar elective operations. Cumulative survival at 48 months was equal to that of the overall hemodialysis population not having cardiac operations. The mean age (50 years), male to female ratio (9:1), number of vessels bypassed per patient (2.4), and operative mortality for ACB were equal to those reported in comparable series of patients with normal renal function. Cumulative survival at 48 months for ACB patients was similar (60% versus 56%) to that of the overall hemodialysis population. Cardiac operations can be performed safely in patients with end-stage renal disease; the morbidity and mortality are similar to those encountered in patients with normal renal function. The long-term survival after cardiac procedures in patients with end-stage renal disease is similar to that reported for the overall hemodialysis population not having cardiac operations.

Soft-tissue reconstruction following extravasation of chemotherapeutic agents.

The incidence of chemotherapeutic extravasation injuries ranges from 0.5% to 6%. Chronicity and an indolent course are prominent characteristics of such wounds, as are severe pain and ulceration with no tendency to spontaneous healing. Prevention is the best treatment. Aggressive surgical debridement is recommended for patients with persistent pain or ulceration. Whirlpool therapy, wet-to-dry dressing changes, and a vigorous physical therapy program are all helpful. Soft-tissue coverage can be obtained by skin grafting, delayed flaps, various local muscle or fasciocutaneous flaps, or by free tissue transfer.

Benign skin and soft-tissue tumors of the hand.

Tumors of the hand are relatively rare when compared to other body regions; the majority are benign in nature. Skin and soft-tissue benign tumors can be classified according to their tissue or origin. Proper diagnosis and differentiation of benign from premalignant or malignant lesions are the most important steps in the management of hand tumors. Surgical excision under adequate anesthesia with histologic diagnosis is the commonest and most accepted treatment.

Refinements in mandibular reconstruction.

The new advances in the application of the prevascularized bone grafts, i.e., fibula and inner cortex iliac crest, have contributed a major advance in the field of mandibular reconstruction. Better understanding of rigid skeletal fixation and its ability during vascularized bone graft transfers further enhances flap survival and patient rehabilitation. Additional advances in techniques of osteointegration, TMJ reconstruction, and soft-tissue reconstruction have greatly augmented our ability for further refinements in this field.

Pediatric microsurgery. Replantation, revascularization, and obstetric brachial plexus palsy.

Revascularization and replantation of the amputated part is absolutely recommended for restoration of function, form, and future growth. From the beginning, microsurgery has been employed to treat children and infants, but as a group pediatric patients have not received much attention. This article discusses several areas in which reconstructive microsurgery plays a prominent role in the pediatric patient.

Pediatric microsurgery. Reconstruction by free tissue transfer.

In the pediatric population, microsurgery has helped to overcome two of the problems particular to this group: the smaller size of their vessels and nerves and the need for future growth. Microsurgery will continue to play a major role in many difficult reconstructive problems in pediatrics in the future.

The iliac crest microsurgical free flap in mandibular reconstruction.

Development of the iliac crest microsurgical free flap has significantly enhanced the surgical restoration of the mandible. A decade of heavy clinical use has established the versatility and efficacy of this technique. A recent literature review suggests a 96% success rate has been achieved. This donor site provides a long vascular pedicle, appropriately shaped bone, skin, and soft tissue. These properties enable tailoring of the flap to precisely fit the defect. The flap has overcome bone size and movement restrictions imposed by regional pedicles. The retained blood supply induces rapid fracture-like healing and provides metabolic independence from the recipient bed. Incorporating an internal oblique muscle island enhances flap utility. The muscle provides a source of oral lining and sanctions the reconstruction of compound defects with a single flap. In an effort to refine the bony component and reduce donor site morbidity, the principal author has introduced the split inner cortex modification. This method has eliminated abdominal wall weakness and hernia, while improving postoperative pelvic contour. The split inner cortex microsurgical iliac crest free flap is the current standard for oromandibular reconstruction in our institution. Additional refinements to internal fixation, TMJ restoration, and osseointegration have resulted in a more refined, comprehensive reconstruction.

Gene therapy for plastic and reconstructive surgery.

In the future, gene therapy will become the standard treatment for enhancing wound healing and nerve and muscle regeneration and for preventing or treating vessel thrombosis, areas critical to the plastic surgeon and the patient. This review has focused on factors that are either currently used in a clinical situation or have the promise of being developed for clinical use. The role of gene therapy applied to these areas will be to locally place therapeutic genes at the site of injury or surgical repair, which will replace the need to systemically administer therapeutic agents that may have toxic effects, and to express factors in low abundance but at effective and safe levels. This strategy is to produce enough agent to have a therapeutic effect. The use of tissue-specific promoters will be beneficial in localizing the production of agents to certain cell types. Gene therapeutic approaches used in plastic surgery may have a significant impact on the health care system by increasing efficiency of treatment and reducing health care costs. The accelerated pace of basic research in gene therapy will result in clinical applications in the near future.

Brachial plexus birth injuries and current management.

OBPP is a condition that, for the majority of patients, resolves spontaneously with appropriate nonoperative treatment. However, those patients who do not improve spontaneously now have a better chance for recovery owing to recent advances in microsurgery and nerve-transfer techniques. The most important aspect of therapy is timely recognition and referral.

Free-tissue transfer with the aid of loupe magnification: experience with 251 procedures.

Eight years ago, the principal author (Shenaq) began employing high-power ocular loupes for microvascular anastomoses. Subsequently, 251 free-tissue transfers were performed with loupes as the sole means of magnification. Procedures included free flaps, toe-to-hand transfers, and digital replantations, with the external diameter of the vascular pedicles averaging 1.5 mm. Analysis of the series revealed a 97.2 percent overall success rate, a 1.2 percent partial flap necrosis rate, and an 8.3 percent revision rate for anastomoses (during the initial operative procedure), which compare favorably with the success rates frequently cited for microscope-assisted procedures. The most favorable results were achieved with free flaps and toe-to-hand transfers with 98.5 and 96.4 percent success rates, respectively. The 79.2 percent survival rate achieved with digital replantation falls within the range (74.0 to 94.2 percent) reported in the literature. This experience indicates that in practiced hands, high-power ocular loupes provide an alternative to the operating microscope for microvascular anastomosis of vessels 1.0 mm or greater in diameter. Loupe use is advocated on the grounds of cost-effectiveness, portability, and operator freedom.

Salvage of amputation stumps by secondary reconstruction utilizing microsurgical free-tissue transfer.

During a 2-year period, 15 lower and upper extremity amputees were treated by microsurgical free-tissue transfer in an effort to salvage their amputation stumps. Salvage of length and restoration of contour to aid in prosthetic rehabilitation were the two main indications for reconstruction. Included in the 15 transfers were 3 scapular free flaps, 11 latissimus dorsi musculocutaneous flaps, and 1 groin flap. Thirteen of the patients in this group were refitted with prostheses following reconstruction and did well with no pain or skin breakdown of the resurfaced stumps. The follow-up period on these patients averaged 16 months. One patient, in whom the flap succeeded, underwent stump soft-tissue revision and myodesis. One patient, in whom the flap failed, continued to develop recurrent ulceration in his stump. This clinical experience followed an extensive laboratory study of 12 above-knee amputation patients using noninvasive Doppler ultrasound measurements to determine weight-loading and interface-pressure distribution between the stump and the socket of the prostheses and their relation to stump length and circumference.

Closure of upper extremity soft-tissue defects using the new "supra-crest" fasciocutaneous free flap.

A fasciocutaneous island (15 x 10 cm) can be elevated from the inferolateral abdominal wall in a region encompassing the iliac crest and extending to the lower costal margin. This new fasciocutaneous flap was named the "supra-crest flap," in accordance with its anatomic location and vascular pattern. The blood supply stems from the direct cutaneous branches of the lumbar arteries (L2-3), which pierce the abdominal musculature approximately 2.0 cm above the iliac crest in the midaxillary line. The arteries and two vena comitantes have an average external diameter of 2.0 mm, and their dissection can be extended deep into the iliac fosa to provide a pedicle 8 or more cm in length. Two cutaneous nerves accompany the lumbar arteries, furnishing the possibility of a sensate flap. These structures have been transferred as a free flap with the donor site concealed by conventional underwear and bathing suits. Additionally, this region could be harvested as an island flap wherein the arc of rotation may be sufficient to cover defects of the thoracic wall and lumbosacral regions.

A new design of the iliac crest microsurgical free flap without including the "obligatory" muscle cuff.

The iliac crest free flap has undergone a gradual evolution to provide more functional and cosmetic oromandibular reconstructions. The soft-tissue cutaneous component has largely resisted refinement and currently constitutes the flap's principal drawback. Conventionally, the cutaneous vessel's soft-tissue encasement and a protective cuff of abdominal muscle are harvested to ensure skin perfusion. These protective measures, however, produce a bulky flap that is tethered to the bone and difficult to inset into complex three-dimensional defects. A series of anatomic and clinical investigations has confirmed that in 30 percent of individuals, the skin island can be elevated on a dominant cutaneous branch from the deep circumflex iliac artery. Harvesting the skin as an axial pattern flap greatly increases its independence from the bone, improving maneuverability. A small collar of abdominal muscle is incised around the pedicle, obviating the need for the customary 2.5-cm protective muscle cuff. Exclusion of the abdominal muscular component reduces the flap's volume, decreases the need for secondary debulking, and reduces the donor site morbidity.

The subcutaneous pedicle tensor fascia lata flap.

The presence of a consistent subcutaneous vascular plexus allows carrying of a distal skin island safely on the iliotibial tract. A distal skin island can be designed on the lateral thigh and can be raised on a subcutaneous pedicle that is proximally supplied by the lateral femoral circumflex artery. This technique preserves the lateral thigh skin and employs subcutaneous tunneling to overcome the traditional drawbacks of the conventional extended tensor fascia lata flap. The subcutaneous pedicle tensor fascia lata flap's sensate potential, thin skin, durable fascia, extensive reach, and 360 degree arc of rotation make it an appealing donor site for coverage of lower midsection and pelvic defects or for penile reconstruction.

Use of human amnion for microvascular interpositional grafts.

A major problem associated with vascular grafting employing an artificial graft is the inflammatory response provoked by the graft and subsequent complications of classical acute rejection phenomena when the graft is implanted subcutaneously into human volunteers. The favorable results obtained by a preliminary study of subcutaneous implantation of amnion in our laboratory have led us to a prospective study to determine its value as a vascular graft. Tubed conduits of glutaraldehyde-treated amnion were hand constructed of varying diameters and lengths. They were employed as segmental interpositional grafts in experimentally created femoral and aortic arterial defects in Sprague-Dawley rats. Patency rates varied from 60 to 90 percent, with all grafts showing remarkable reendothelialization within 3 to 4 weeks postoperatively. Morphology, antigenic reaction, blood flow, and patency of the different experimental amnion grafts were evaluated and compared to appropriate controls.

Prefabricated flaps: experimental and clinical review.

Prefabricated flaps are a useful tool for the reconstructive surgeon and present a number of advantages: 1. Specific preferred tissue composites, regardless of their native vascular origin, can be transferred as free or pedicled flaps. 2. Larger flaps of specialized tissue may be transferred safely. 3. Donor-site morbidity is reduced. 4. The functional outcome for the patients may be more satisfactory. The various methods of flap prefabrication include vascular induction through stage transfer; pretransfer delay, expansion, and grafting; the use of alloplastic materials; and tissue bioengineering. We have reviewed both the experimental and clinical research on flap prefabrication, describing the theory, technique, and advantages of each method.

Increased free fat-graft survival with the long-term, local delivery of insulin, insulin-like growth factor-I, and basic fibroblast growth factor by PLGA/PEG microspheres.

The present investigation evaluates the effects of long-term, local delivery of insulin, insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) on fat-graft survival using a poly (lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microsphere delivery system. Twelve-micrometer PLGA/PEG microspheres incorporated separately with insulin, IGF-1, and bFGF were manufactured using a double-emulsion solvent-extraction technique. Inguinal fat from Sprague Dawley rats was harvested, diced, washed, and mixed with (1) insulin microspheres, (2) insulin-like growth factor-1 microspheres, (3) basic fibroblast growth factor microspheres, (4) a combination of the insulin and IGF-1 microspheres, and (5) a combination of insulin, IGF-1, and bFGF microspheres. The treated fat grafts were implanted autologously into subdermal pockets in six animals for each group. Animals receiving untreated fat grafts and fat grafts treated with blank microspheres constituted two external control groups (six animals per external control group). At 12 weeks, all fat-graft groups were compared on the basis of weight maintenance and a histomorphometric analysis of adipocyte area percentage, indices of volume retention and cell composition, respectively. Weight maintenance was defined as the final graft weight as a percent of the implanted graft weight. All growth factor treatments significantly increased fat-graft weight maintenance objectively, and volume maintenance grossly, in comparison with the untreated and blank microsphere-treated controls. Treatment with insulin and IGF-1, alone or in combination, was found to increase the adipocyte area percentage in comparison with fat grafts treated with bFGF alone or in combination with other growth factors. In conclusion, the findings of this study indicate that long-term, local delivery of growth factors with PLGA/PEG microspheres has the potential to increase fat-graft survival rates. Further, the type of growth factor delivered may influence the cellular/stromal composition of the grafted tissue.

De novo adipose tissue generation through long-term, local delivery of insulin and insulin-like growth factor-1 by PLGA/PEG microspheres in an in vivo rat model: a novel concept and capability.

This study was undertaken to characterize the duration of long-term growth factor delivery by poly(lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microspheres and to evaluate the potential of long-term delivery of insulin and insulin-like growth factor-1 (IGF-1) for the de novo generation of adipose tissue in vivo. PLGA/PEG microspheres containing insulin and IGF-1, separately, were produced by a double-emulsion solvent-extraction technique. In the first phase of the experiment, the in vitro release kinetics of the microspheres were evaluated for the optical density and polyacrylamide gel electrophoresis of solutions incubated with insulin-containing microspheres for four different periods of time (n = 1). The finding of increased concentrations of soluble insulin with increased incubation time confirmed continual protein release. In the second stage of the experiment, 16 rats were divided equally into four study groups (insulin, IGF-1, insulin + IGF-1, and blank microspheres) (n = 4). Insulin and IGF-1 containing microspheres were administered directly to the deep muscular fascia of the rat abdominal wall to evaluate the potential for de novo adipose tissue generation via adipogenic differentiation from native nonadipocyte cell pools in vivo. Animals treated with blank microspheres served as an external control group. At the 4-week harvest period, multiple ectopic islands of adipose tissue were observed on the abdominal wall of the animals treated with insulin, IGF-1, and insulin + IGF-1 microspheres. Such islands were not seen in the blank microsphere group. Hematoxylin and eosin-stained sections of the growth factor groups demonstrated mature adipocytes interspersed with fibrous tissue superficial to the abdominal wall musculature and continuous with the fascia. Oil-Red-O stained sections demonstrated that these cells contained lipid. Computer-aided image analysis of histologic sections confirmed that there were statistically significant increases in the amount of "ectopic" adipose neotissue developed on the abdominal wall of animals treated with growth factor microspheres. In conclusion, this study confirms the long-term release of proteins from PLGA/PEG microspheres up to 4 weeks and demonstrates the potential of long-term local insulin and IGF-1 to induce adipogenic differentiation to mature lipid-containing adipocytes from nonadipocyte cell pools in vivo at 4 weeks.