Enhancement of epidermal regeneration by biosynthetic epidermal growth factor.

Epidermal regeneration depends on mitosis and migration of keratinocytes. Epidermal growth factor is known to stimulate growth of keratinocytes in vitro, thus it might be expected to promote wound healing. The results of this study show that topical application of biosynthetic human epidermal growth factor accelerates epidermal regeneration in split-thickness wounds and partial-thickness burns. The significant enhancement of epidermal regeneration suggests the potential for clinical use of epidermal growth factor for accelerating healing of burns, wounds from trauma, diabetic ulcers, skin graft donor sites, and others.

The history of human composite tissue allotransplantation.

Restoration of amputations and disfigurement are represented in ancient mythology, but the modern history of composite tissue allotransplantation begins with World War II injuries that generated seminal immunologic experiments by Medawar and co-workers. These studies led to the first successful human allografts in the 1950s by Peacock with composite tissue and Murray and co-workers with solid organs. Pharmacologic immunosuppression brought rapid growth of solid organ transplantation over the next 50 years, but composite tissue transplantation virtually disappeared. This evolution was judged to be a consequence of the greater antigenicity of skin, which that was insurmountable by the available immunosuppression. In the mid-1990s, progress in immunosupression allowed skin-bearing grafts, led by successful hand transplants, which produced a renaissance in composite tissue allotransplantation. Since then, graft types have expanded to over 10, and graft numbers to over 150, with success rates that equal or exceed solid organs. The field has emerged as one of the most exciting in contemporary medicine, although accompanied by substantial challenges and controversy. This paper reviews the origins and progress of this field, assessing its potential for future evolution.

Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program.

This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.

Reconstruction of complex thoracic defects with myocutaneous and muscle flaps. Applications of new flap refinements.

This report describes reconstructions of complex thoracic defects with myocutaneous and muscle flaps that were modified by several recent refinements of flap design. These refinements comprise a second generation of myocutaneous and muscle flaps, which have substantially increased versatility and extended applications, as compared with the originally described flaps. These refinements include the following: (1) segmentally split latissimus dorsi and pectoralis major flaps, which transfer only one muscle segment as the flap and leave other segments of the same muscle in situ to preserve motor function; (2) pectoralis major fasciocutaneous flaps, which are extended by abdominal skin and fascia to provide longer, larger flaps; (3) reversed pectoralis major and latissimus dorsi flaps, which are supplied by secondary, distal vascular pedicles that permit flap use when the primary vascular supply is interrupted; and (4) island vascular pedicle muscle flaps, which allow intercostal passage for reconstruction of intrathoracic defects and cavities. The anatomic bases for these flap refinements are described, and the advantages provided are discussed.

Collagen biosynthesis in healing wounds of the spinal cord and surrounding membranes.

Kinetics of collagen synthesis and deposition were studied in the canine spinal cord, pia mater, and dura mater and in wounds of these tissues over the first 8 weeks. Little collagen is present in unwounded spinal cord compared with surrounding mesenchymal membranes. Collagen synthetic potential was found within the spinal cord, a tissue of neurectodermal origin. Rate of collagen synthesis per collagen content in the unwounded spinal cord was high. This synthetic rate was as high as that of wounds at their maximum collagen synthetic rates. Substantial deposition of collagen followed spinal cord wounding. Wounding the spinal cord, pia mater, and dura mater caused substantial elevations in rates of collagen synthesis in each tissue. These synthetic rates remained at maximum levels throughout the 8-week study, a prolonged period when compared with other wounded tissues previously studied. The role of mesenchymal tissue physiology in central nervous system wound healing is discussed. The potential value of these findings for further studies and for experimental manipulation of the healing process in spinal cord and central nervous system wounds is presented. Implications of these findings on the hypothetical relationship of scar to spinal cord and central nervous system regeneration are noted.

Epithelial lining methods in esophageal repair: a comparative study using pedicle flaps in cats.

Methods of restoring luminal lining in repair of partial-circumferential esophageal defects were evaluated to compare incidences of strictures and fistulas and quality of surface lining. In cats 50% and 67% circumferential esophageal defects were repaired by direct closure or pedicle flaps (latissimus dorsi) that were unlined (lining restored by epithelialization from wound margins) or that carried lining of normal skin (myocutaneous flaps), skin grafts, or mucosal grafts. Repairs were evaluated for esophagocutaneous fistulas, luminal stricture, flap luminal surface area, and quality of epithelial surface 6 weeks after surgery. Direct closure of 50% circumferential defects was as satisfactory as any flap repair method. Direct closure of 67% circumferential defects caused high incidences of fistulas and strictures, which were lessened by flap reconstructions. Among flap lining methods, normal skin (myocutaneous flaps) gave the lowest incidence of fistulas and strictures and the highest surface quality, but a high incidence of skin paddle loss occurred in this model. Split-thickness epithelial grafts were nearly as satisfactory as myocutaneous flaps, and less lining loss occurred. Epithelialization of unlined flaps gave the poorest results since lining was thin and often incomplete, and wound contraction produced loss of surface area and strictures. The findings are discussed from a perspective of wound healing physiology, and implications for clinical application are presented.

Closure of esophageal defects with muscle flaps.

OBJECTIVE: To determine the feasibility and reliability of muscle flaps as a sole means of closure of severe esophageal defects. DESIGN: Retrospective case series of patients with esophageal defects closed with muscle flaps. Mean follow-up was 6 years. SETTING: A university hospital and a tertiary care, university-affiliated, private hospital. PATIENTS: Fourteen patients with esophageal defects that could not be closed by standard suture techniques or failed to close with observation alone. MAIN OUTCOME MEASURES: Survival, continued esophageal leakage, restoration of esophageal continuity, and long-term esophageal function. RESULTS: There was one operative death and one delayed death, both unrelated to the esophageal injury. There were five early leaks that healed promptly. Esophageal continuity was restored in all patients. Long-term esophageal function has been excellent. CONCLUSIONS: The use of primary muscle repair for esophageal defects not amenable to standard closure techniques provides an excellent means of closing esophageal wounds and restoring esophageal continuity. This option appears to be preferable to other more destructive options in managing this serious problem.

A neuromuscular basis for development of indirect inguinal hernia.

Specialized portions of the transversus abdominus muscles act on the internal inguinal rings and produce a closure mechanism during voluntary abdominal muscular activity. Abdominal muscular contractions may have a protective influence against development of indirect inguinal hernia. It follows, therefore, that injury or inactivation of this mechanism may be an etiologic factor in the development of indirect inguinal hernia. One cause of injury to this mechanism is by denervation and regional muscle paralysis occurring during a surgical procedure. Surgical denervation appears to have caused an indirect inguinal hernia in one of the authors.

One-stage simple mastectomy with immediate reconstruction for high-risk patients. An improved technique: the biologic basis for ductal-glandular mastectomy.

The heterogeneity of human breast carcinoma appears to be a cumulative interrelationship of genetic and environmental factors that may be identifiable with a high risk for carcinogenesis. Until breast cancer prevention is realized, one-stage total ductal-glandular mastectomy with immediate reconstruction may be offered as an alternative to simple mastectomy for women at high risk for developing cancer. This technique affords the complete extirpation of breast tissue at a deep plane with flaps that are identical in thickness to those elevated in classic mastectomies for invasive cancer. Breast reconstruction with submuscular prostheses in a one-stage procedure gives an aesthetically acceptable result. The role of ductal-glandular mastectomy as prophylaxis for invasive carcinoma warrants future prospective trials.

Use of the rhomboid major muscle flap for esophageal repair.

A 16-year-old boy sustained vehicular blunt trauma with delayed esophageal rupture that resulted in empyema and an esophagopleurocutaneous fistula. Diverting esophagostomy, gastrotomy, and transpyloric jejunostomy were performed, and these procedures permitted satisfactory nutritional support of the patient. Staged direct closure of the esophagus buttressed by a rhomboid muscle flap preserved normal esophageal function. Both clinical application and cadaver dissections have demonstrated that the rhomboid flap has an excellent blood supply and that it can be used to repair lesions on either side in the upper half of the esophagus. Because this flap is extrathoracic, it is not usually distorted by intrathoracic sepsis or previous thoracic incisions. The rhomboid major muscle flap is an excellent alternative to conventional autogenous grafts for esophageal repair.

Vascularized muscle flaps for life-threatening mediastinal wounds in children.

Vascularized muscle flaps have been shown to be highly effective in adults for complicated mediastinal and thoracic wounds. They result in infection control, wound coverage, and preservation of life. Minimal experience exists with the use of these techniques in children. We review our experience with vascularized muscle flaps between 1985 and 1993 in treating life-threatening mediastinal wounds in 8 children. The 8 patients ranged in age from 1 day to 10 years; mean age was 2 years. Two patients had mediastinitis; one had an exposed Gore-Tex graft, and the other had an exposed homograft conduit. One patient had a midline defect with exposed right ventricle immediately beneath the skin. One patient had tracheal dehiscence after repair of an acquired tracheoesophageal fistula from battery erosion. One patient with Marfan's syndrome had a pectus deformity and an unstable sternum after emergent reoperation for a false aortic aneurysm. Two neonates had their sternum left open with a temporary Silastic skin patch after orthotopic cardiac transplantation because of swelling of the donor heart. One transplant patient had wound dehiscence. Vascularized muscle flaps used to heal the mediastinal wounds in this group included pectoralis major (10), rectus abdominis (3), and cervical strap (1). One infant with asplenia and an exposed Gore-Tex graft that had a delayed vascularized muscle flap died of Candida sepsis. Seven of 8 patients (85%) healed their mediastinal wound. Prompt recognition of thoracic wound complications facilitates immediate surgical intervention to obtain primary closure with vascularized muscle flaps, which promotes rapid healing in these children.

Correction of anomalous subdiaphragmatic inferior vena caval drainage of the right pulmonary veins (scimitar syndrome).

Correction of anomalous infradiaphragmatic inferior vena caval drainage of the right pulmonary veins can be repaired under conventional cardiopulmonary bypass by placing a circumferential tape below the diaphragm between the hepatic veins and the scimitar vein entrance. During repair, creation of an atrial septal defect in the distorted septal-left atrial junction of scimitar syndrome is facilitated by first incising the anteromedial aspect of the fossa ovalis to better delineate the optimal posterolateral margin. A case history illustrates the technique.

Management of extensive right ventricular injury or rupture.

Most penetrating right ventricular injuries require simple suture repair, but more extensive injury or rupture of the right ventricle may not be amenable to this method. We have developed an approach to the problem and a technique for repair. Compression of the area with early institution of cardiopulmonary bypass will result in decompression of the right ventricle and preservation of perfusion, preventing profound hypotension. Coverage with an onlay autologous tissue patch provides hemostatic control of the defect without compromising ventricular function. Reinforcement with omentum or muscle flap can give additional protection when risk of infection is present. Application of these principles can be lifesaving and insure good cardiac function despite massive injury to the right ventricular myocardium.

Serious wound infections after minimally invasive coronary bypass procedures.

BACKGROUND: Minimally invasive coronary artery bypass grafting has become an increasingly accepted therapy for selected patients with single-vessel coronary artery disease. Reported morbidity has focused on anastomotic problems, but the occurrence of serious wound complications after these procedures has not been well documented. METHODS: We reviewed our institutional experience with 35 patients to look for the incidence of serious wound complications. RESULTS: Three patients had serious wound problems after minithoracotomy for coronary artery bypass graft procedures. This represents an overall 9% wound morbidity rate and a 100% rate in the obese women. CONCLUSIONS: Wound complications at the incision site after minithoracotomy coronary artery bypass graft procedures seem to occur distinctly in obese women with redundant breasts.

Vascular delay of the latissimus dorsi provides an early hemodynamic benefit in dynamic cardiomyoplasty.

OBJECTIVES: Dynamic cardiomyoplasty (CMP) as a surgical treatment for chronic heart failure improves functional class status for most patients. However, significant hemodynamic improvement with latissimus dorsi muscle (LDM) stimulation has not been consistent. The current protocols do not allow early LDM stimulation after CMP surgery. We hypothesized that vascular delay of LDM would increase myocardial assistance after CMP and allow early (48-h) LDM stimulation after CMP. METHODS: Mongrel dogs (n = 24) were divided in four groups: 1) controls (n = 6), single-stage CMP; 2) Group ES (n = 6), single-stage CMP with early LDM stimulation beginning 48 h, postoperatively; 3) Group VD (n = 6), vascular delay of the LDM followed by CMP without early LDM stimulation, and 4) Group VDES (n = 6), vascular delay of LDM (14-18 days), followed by CMP with early stimulation (48 h postoperatively). Two weeks after CMP, global cardiac dysfunction was induced by injecting microspheres into the left coronary artery. LDM-assisted (S) beats were compared with nonstimulated beats (NS) by measuring aortic pressure (AoP), LV pressure, aortic flow, and by calculating first derivative of LV contraction (+/-dP/dt), stroke volume (SV), and stroke work (SW). RESULTS: In ES, LDM stimulation had no effect on the hemodynamic parameters. In the other groups, LDM stimulation significantly (p < 0.05) increased AoP, LVP, dP/dt, SV, and SW. However, these increases were much larger in VD and VDES. In VD, LDM stimulation increased peak AoP by 21.5+/-3.8 mm Hg, LVP by 22.1+/-4.1 mm Hg, dP/dt by 512+/-163 mm Hg/sec, SV by 10.4+/-2.3 mL, and SW by 22.1+/-5.4 g/m(-1). Similarly, in VDES, LDM stimulation increased peak AoP by 24.1+/-4.7 mm Hg, LVP by 26.2+/-4.3 mm Hg, dP/dt by 619+/-47 mm Hg/sec, SV by 6.5+/-0.7 mL, and SW by 16.7+/-4.1 g/m(-1). CONCLUSIONS: In dogs with global LV dysfunction, CMP after vascular delay resulted in a significant improvement in hemodynamic function measured 2 weeks after surgery. This improvement was not provided by single-stage CMP with or without early stimulation. Vascular delay of the LDM before surgery may play an important role for early benefit after CMP, shorten the overall muscle training period, as well as increase hemodynamic response to LDM stimulation.

Vascular delay of the latissimus dorsi muscle: an essential component of cardiomyoplasty.

BACKGROUND: Cardiomyoplasty (CMP) uses the latissimus dorsi muscle (LDM) to assist the heart in cases of cardiac failure. Distal ischemia and necrosis of the LDM is a recognized complication of CMP that can reduce distal muscle function and the mechanical effectiveness of CMP. METHODS: Canine (n = 9) LDMs were subjected to a 10-day period of vascular delay followed by a simulated CMP. Two weeks after simulated CMP (corresponding to the healing delay between CMP and the onset of LDM stimulation used in the clinical setting), LDM perfusion was measured in the distal, middle, and proximal segments of the muscle, and circumferential (distal and middle squeezing muscle function) and longitudinal (proximal pulling muscle function) force generation and fatigue rates were measured. The results were compared with the contralateral nondelayed simulated CMP. RESULTS: Muscle perfusion was significantly (p < 0.05) greater in the distal and middle segments of vascular-delayed LDMs. Circumferential muscle force generation and fatigue rates were significantly (p < 0.05) improved in the vascular-delayed LDMs. CONCLUSIONS: Vascular delay can significantly improve LDM perfusion and function in a model that closely reflects clinical CMP, and the use of vascular delay may improve clinical outcomes in CMP.

Comparison of the effects of commonly used wound agents on epithelialization and neovascularization.

BACKGROUND: The primary effect sought with most topical wound therapy is antimicrobial. Topical wound agents are thought to promote normal healing by protecting the wound from infection. In this study, we examined the effect of six commonly used topical wound agents (bacitracin, sodium hypochlorite, silver nitrate, silver sulfadiazine, mafenide acetate, and povidone-iodine) on epithelialization and neovascularization in noninfected wounds. For this study, a new wound model was used in which direct visualization and quantification of wound epithelialization and neovascularization were carried out throughout the entire healing process. STUDY DESIGN: We measured the effect which 500 U per g of bacitracin, 0.25 percent of sodium hypochlorite, 0.5 percent silver nitrate, 1 percent silver sulfadiazine, 8.5 percent mafenide acetate, and 10 percent povodione-iodine had on the rate of wound epithelialization and neovascularization. The agents were applied topically to 99 circular full-thickness wounds (2.25 mm diameter, 0.125 mm depth) created on the dorsum of male hairless mouse ears. This model enabled us to visualize and measure directly wound epithelialization and neovascularization repeatedly throughout healing, using intravital video microscopy and computerized digitized planimetry. RESULTS: Control wounds and wounds treated with silver sulfadiazine (n = 18) and mafenide acetate (n = 14) epithelialized in 7.2 +/- 0.7, 7.1 +/- 0.3, and 7.3 +/- 0.3 days, respectively. This was significantly (p < 0.01) faster than the wounds treated with povidone-iodine (n = 10), sodium hypochlorite, (n = 8), and bacitracin (n = 13). Wounds treated with povidone-iodine epithelialized the slowest (11.8 +/- 0.55 days). Wound neovascularization was completed most rapidly in the groups treated with povidone-iodine and silver sulfadiazine (15.0 +/- 0.4 and 15.3 +/- 0.7 days, respectively). This was significantly (p < 0.05) faster than wounds treated with silver nitrate (n = 15), which neovascularized in 18.4 +/- 0.56 days. One-half of the wounds treated with sodium hypochlorite (eight of 16) did not epithelialize or neovascularize. CONCLUSIONS: The various antimicrobial agents studied in our in vivo model affect wound epithelialization and neovascularization differently. These effects on these two very important aspects of healing should be taken into consideration when indicating a specific agent for treatment of different types of wounds.

Impediments to wound healing.

Chronic wounds will often heal in a short period of time if factors that inhibit wound healing are identified and managed. Recombinant growth factor therapy may provide an added stimulus to healing in certain types of chronic wounds. However, there remains no substitute for a physiologic environment conducive to tissue repair and regeneration, without which the efficacy of growth factor therapy is questionable. Some of the most commonly encountered and clinically significant impediments to wound healing include wound hypoxia, infection, presence of debris and necrotic tissue, use of anti-inflammatory medications, a diet deficient in vitamins or minerals, or general nutritional deficiencies, tumors, environmental factors, and metabolic disorders, such as diabetes mellitus. Treatment of chronic wounds should be directed against the main etiologic factors responsible for the wound. Moreover, factors that may impede healing must be identified and, if possible, corrected, for healing to occur.

Physiology and healing dynamics of chronic cutaneous wounds.

In the last few decades, a great deal of progress has been made in understanding the cellular and biochemical interplay that comprises the normal wound healing response. This response is a complex process involving intricate interactions among a variety of different cell types, structural proteins, growth factors, and proteinases. The normal wound repair process consists of three phases--inflammation, proliferation, and remodeling--that occur in a predictable sequence and comprise a series of cellular and biochemical events. A review of the biochemical and physiologic processes that regulate wound healing and the cascade of cellular events that gives rise to the healing process is presented here.

One-stage pharyngoesophageal and oral mucocutaneous reconstruction with two segments of one musculocutaneous flap.

This report describes a one-stage technique that provides both cover and lining to mucocutaneous defects of the head and neck with either latissimus dorsi or pectoralis major musculocutaneous units that are split into anatomic segments to create two independent flaps from one musculocutaneous unit. In addition, this technique further refines reconstruction of pharyngoesophageal defects. Techniques of simultaneous mandibular reconstruction with vascularized bone carried on these same segmental flaps are also commented on.