Scar formation: the spectral nature of fetal and adult wound repair.
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Adult↗
Biomedical subjects
M T Longaker
Publications and source records attributed to M T Longaker.
Delayed in utero repair of surgically created fetal cleft lip and palate.
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Animals↗
Microsurgical correction of facial contour in congenital craniofacial malformations: the marriage of hard and soft tissue.
The correction of facial asymmetry in complex craniofacial malformations presents a challenging problem for reconstructive surgeons. Deficiencies of both the facial skeleton and the overlying soft tissue must be addressed to achieve the optimal reconstructive result. We present our experience with a minimum of 1-year follow-up over a 5-year period with 19 patients who initially underwent standard facial skeletal reconstruction and subsequently required microsurgical soft-tissue reconstructions for final correction of facial contour. From July of 1989 to June of 1994, 19 patients with craniofacial malformations underwent microsurgical correction of facial contour using 21 free flaps. The underlying malformations included 15 hemifacial microsomias, 2 orbitofacial clefts, 1 congenital temporomandibular joint ankylosis with micrognathia, and 1 Tessier no. 30 (lower midline mandibular) cleft. Sixteen patients had previous facial skeletal correction using craniofacial techniques. Age at operation ranged from 6 to 27 years. Twenty-one microvascular flaps were used on the 19 patients: 19 deepithelialized parascapular flaps, 1 superficial inferior epigastric flap, and 1 fibula with soleus muscle and large skin paddle for a severe Tessier no. 30 facial cleft with severe micrognathia. Of the 15 patients with hemifacial microsomia, 10 were treated with parascapular fasciocutaneous flaps, 3 with parascapular flaps with bone, 1 with a parascapular flap with teres major muscle for additional bulk, and 1 with a superficial inferior epigastric flap. Complications were two limited hematomas drained at the bedside and a partial skin paddle slough of the fibula flap. Correction of facial contour in complex craniofacial malformations is possible using microsurgical techniques. These free flaps "camouflage" the underlying skeletal deformity that persists despite traditional skeletal reconstruction while restoring symmetrical facial contour. We recommend the marriage of both skeletal and microsurgical soft-tissue reconstructions to achieve the optimal aesthetic result for craniofacial contouring in these challenging patients.
Adolescent↗
Microsurgical correction of bilateral facial contour deformities.
Bilateral facial contour deformities are difficult reconstructive problems to correct. This paper summarizes our experience with five adult patients who were operated on for the correction of bilateral contour deformities. The etiologies of the contour deformities were one case of systemic lupus erythematosus, three cases of hemangioma/lymphangiomas, and one case of systemic lipodystrophy. Patient ages at the time of surgical correction ranged from 19 to 65 years. In two patients, staged microvascular free-tissue transfers were performed. In three patients, a single free flap was used for reconstruction. Seven microvascular free flaps were used to reconstruct facial contour: three superficial inferior epigastric flaps and four inframammary extended circumflex scapular flaps. In three patients, recipient sites were dissected by means of a limited preauricular incision, and the superficial temporal artery and vein were utilized as recipient vessels. The two remaining patients underwent free-tissue transfer to branches of the external carotid system. There were no flap losses in this series. Follow-up ranged from 1 to 4 years. A stable restoration of facial contour was achieved in all five patients. Microsurgical correction of soft-tissue contour problems is possible in bilateral deformities, and superior results are easier to achieve than in unilateral facial contour deformities. Either single or staged reconstructions can restore facial contour depending on the distribution of soft-tissue requirements.
Adult↗
Studies in cranial suture biology: IV. Temporal sequence of posterior frontal cranial suture fusion in the mouse.
The biology underlying normal and premature cranial suture fusion remains unknown. To develop a model for normal cranial suture fusion, the temporal sequence of the posterior frontal cranial suture fusion in the mouse was determined. To do this, all the cranial sutures of three distinct strains of mice (CD-1, CF-1, and C57bl-6) were studied histologically for fusion at sequential time points. Two studies were set up using group A mice (n = 72, all sutures studied) and group B mice (n = 78, only the posterior frontal suture studied, but more precisely along its anatomic length). In the group A cranial suture study, mice were sacrificed starting at newborn age and then every 5 days until age 50 days. In addition, two mature mice (250 days old) from each strain were sacrificed. In all three mouse strains, histologic examinations showed that the anterior frontal, sagittal, coronal, lambdoid, and occipitointerparietal sutures remained patent at up to 50 days of age and were patent in the 250-day mature mice. However, examination of the midpoint of the posterior frontal suture showed patency at 30 days, partial fusion at 35 days, and complete fusion by 40 days. These data prompted the posterior frontal suture fusion study. In the group B posterior frontal suture fusion study, mice were sacrificed at age 23 days and then every 2 days until 47 days of age. The anterior, midpoint, and posterior aspects of the posterior frontal suture were examined: The anterior aspect fused between 25 and 29 days; the midpoint fused between 31 and 37 days; and the posterior aspect fused between 39 and 45 days. These data indicate that fusion of the posterior frontal cranial suture in the mouse proceeds in a defined temporal sequence from an anterior to posterior direction in three distinct strains of mice, while in the same mice all other cranial sutures remain patent. By describing and understanding the fusion of the normal posterior frontal suture, a biologic basis of normal suture development and fusion can be established and used as a comparison for murine cranial sutures altered surgically, biochemically (with growth factors), or genetically (with craniosynostotic phenotypes).
Animals↗
Studies in cranial suture biology: in vitro cranial suture fusion.
The biology underlying craniosynostosis remains unknown. Previous studies have shown that the underlying dura mater, not the suture itself, signals a suture to fuse. The purpose of this study was to develop an in vitro model for cranial-suture fusion that would still allow for suture-dura interaction, but without the influence of tensional forces transmitted from the cranial base. This was accomplished by demonstrating that the posterior frontal mouse cranial suture, known to be the only cranial suture that fuses in vivo, fuses when plated with its dura in an organ-culture system. In such an organ-culture system, the sutures are free from both the influence of dural forces transmitted from the cranial base and from hormonal influences only available in a perfused system. For the cranial-suture fusion in vitro model study, the sagittal sutures (controls that remain patent in vivo) and posterior frontal sutures (that fuse in vivo) with the underlying dura were excised from 24-day-old euthanized mice, cut into 5 x 4 x 2-mm specimens, and cultured in a chemically defined, serum-free media. One hundred sutures were harvested at the day of sacrifice, then every 2 days thereafter until 30 days in culture, stained with H & E, and analyzed. A subsequent cranial-suture without dura in vitro study was performed in a similar fashion to the first study, but only the calvariae with the posterior frontal or sagittal sutures (without the underlying dura) were cultured. Results from the cranial-suture fusion in vitro model study showed that all sagittal sutures placed in organ culture with the underlying dura remained patent. More importantly, the posterior frontal sutures with the underlying dura, which were plated-down as patent at 24 days of age, demonstrated fusion after various growth periods in organ culture. In vitro posterior frontal mouse-suture fusion occurred in an anterior-to-posterior direction but in a delayed fashion, 4 to 7 days later than in vivo posterior frontal mouse-suture fusion. In contrast, the subsequent cranial-suture without dura in vitro study showed patency of all sutures, including the posterior frontal suture. These data from in vitro experiments indicate that: (1) mouse calvariae, sutures, and the underlying dura survive and grow in organ-culture systems for 30 days; (2) the local dura, free from external influences transmitted from the cranial base and hormones from distant sites, influences the cells of its overlying suture to cause fusion; and (3) without dura influence, all in vitro cranial sutures remained patent. By first identifying the factors involved in dural-suture signaling and then regulating these factors and their receptors, the biologic basis of suture fusion and craniosynostosis may be unraveled and used in the future to manipulate pathologic (premature) suture fusion.
Animals↗
Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing.
Recent in situ hybridization studies had demonstrated a strong increase in vascular endothelial growth factor (VEGF) mRNA expression in the hyperproliferative epithelium during wound healing. To determine potential mediators of VEGF induction during this process, we analyzed the regulation of VEGF expression in cultured human keratinocytes. We found a large induction of VEGF expression upon treatment of quiescent cells with serum, epidermal growth factor, transforming growth factor-beta 1, keratinocyte growth factor, or the proinflammatory cytokine tumor necrosis factor alpha, respectively. Since all these factors are present at the wound site during the early phase of wound healing, they might also be responsible for VEGF induction after cutaneous injury. To determine the importance of increased VEGF production for wound repair, we compared the time course of VEGF mRNA expression during wound healing of healthy control mice with the kinetics of VEGF expression during skin repair of genetically diabetic db/db mice which are characterized by impaired wound healing. In normal mice we found elevated VEGF mRNA levels during the period when granulation tissue formation occurs. In contrast, VEGF mRNA levels even declined during this period in db/db mice, suggesting that a defect in VEGF regulation might be associated with wound healing disorders.
Animals↗
Hemodynamic study of different angled end-to-side anastomoses.
This study assessed the postoperative microvascular hemodynamics in end-to-side arterial anastomoses of varied angles in order to determine whether the angle of the anastomosis affects arterial flow. Thirty male rats were divided into three groups of ten. Carotid to carotid end-to-side anastomoses were performed with anastomotic angles of 45, 90, and 135 degrees. Postoperative flow was assessed using high frequency pulsed Doppler ultrasound (HFPDU) at 30 and 120 min postoperatively. Measurements at 30 min demonstrated significant differences in flow, with the 45 degrees grafted vessels utilizing 56.5% of total carotid flow, and the 90 degrees and 135 degrees anastomoses appropriating 46.5% and 43.2% of flow, respectively (comparing 45 degrees to both 90 degrees, P < 0.05, and 135 degrees, P < 0.002). The change from baseline in 45 degrees and 90 degrees groups dissipated over a 2 hr postoperative period, but flow in the grafted vessels in the 135 degrees group continued well below 50% at 39.9% (comparing to both 45 degrees and 90 degrees, P < 0.001), thereby displaying a significant difference in the postoperative arterial flow of varied angled microanastomoses.
Anastomosis, Surgical↗
Arrhythmogenic ventricular aneurysms unrelated to coronary artery disease.
Malignant ventricular tachycardia occurs most frequently in patients with coronary artery disease who have had a previous myocardial infarction and in whom a ventricular aneurysm subsequently develops in the scarred section of myocardium. Ventricular tachycardia in the presence of normal coronary arteries and a left ventricular aneurysm is unusual and can be refractory to medical therapy. We retrospectively reviewed our experience of 10 patients treated at our institution from 1983 to 1993. Age ranged from 22 to 76 years, and all patients presented with sustained ventricular tachycardia. All patients underwent complete electrophysiologic testing. Cardiac catheterization was performed in 9 patients, and each had normal coronary artery anatomy without evidence of significant fixed lesions. A left ventricular aneurysm, diagnosed by either echocardiography, thoracic cine computed tomography or magnetic resonance imaging, or ventricular angiography was present in all patients. Ventricular tachycardia could not be suppressed pharmacologically in 7 of 10 patients using multiple agents including procainamide, quinidine, flecanide, tocainide, propaferone, and amiodarone. Six patients were treated surgically by intraoperative electrophysiologic mapping, endocardial resection of foci, and left ventricular aneurysmectomy. An implantable cardiac defibrillation device was implanted in 2 patients. One patient died on the second postoperative day after simultaneous mapping -guided aneurysmectomy and implantable cardioverter defibrillator placement. There was one late postoperative death. All other surgically treated patients had postoperative electrophysiologic studies demonstrating no inducible ventricular tachycardia, and these patients remain without antiarrhythmic therapy in follow-up extending from 29 to 86 months (mean, 56 months).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Microsurgical reconstruction of the lower extremity using the 3M microvascular coupling device in venous anastomoses.
Microsurgical reconstruction of the lower extremity presents a difficult problem to plastic surgeons; the rate of failure is higher than any other anatomical site. We reviewed our recent experience with lower extremity microsurgical reconstruction using the 3M vascular coupling device. We believe the excellent patency rate of the coupler may minimize the well-described problem of venous thrombosis in this challenging group of patients. This study involves a consecutive series of 11 patients who presented for reconstructive microsurgery of the lower extremity at NYU Medical Center hospitals between June 1 and September 1, 1994. Ten of 11 patients had free flap transfer to traumatic lower extremity injuries, whereas the remaining reconstruction was in a diabetic individual with a chronic wound. Fifteen microvascular venous anastomoses were performed; all but 1 was performed using the 3M coupler. Our experience with 11 patients, involving 14 mechanically coupled venous anastomoses, demonstrated successful use of the coupler. No intraoperative or postoperative vascular complications occurred. The overall success rate of the 3M coupler for venous anastomoses was 100%, and all microvascular free flaps were successful. We recommend using the 3M coupling device for venous anastomoses during reconstructive microsurgery of the lower extremity. Our series demonstrates the safety and effectiveness of the 3M coupler in this challenging group of patients. In addition, a secondary benefit of the 3M coupler is a significant reduction in operative time.
Adolescent↗
Microvascular free-flap correction of severe hemifacial atrophy.
Romberg's disease is a progressive hemifacial atrophy of unknown etiology. Microsurgical reconstruction, focusing on the correction of facial asymmetry and restoration of contour, has become the "gold standard." We report our experience with 15 patients involving 16 free-tissue transfers with a minimum of 1 year of follow-up who were treated from July of 1989 to January of 1993. All patients were classified as having severe atrophy. There were 7 males and 8 females in the series. Distribution of disease was a coup de sabre type or segmental pattern in 6 patients, whereas 9 patients had a hemifacial distribution. Fourteen patients had unilateral disease (7 right and 7 left), and 1 patient had bilateral atrophy. The average age of onset of disease was 11.9 years. The average duration of atrophy was 6.7 years. No patient was operated on with a quiescent interval of less than 2 years. Average age at operation was 28.7 years, with a range from 6 to 46 years. Follow-up ranged from 1 to 4.5 years. Two patients had facial hematomas as the only complication. No flaps were lost. Flap revisions consisting of minor contour corrections were performed in 10 patients. Limited recurrence of facial atrophy was seen in a single patient 2 years postoperatively. All patients rated their improvement as excellent. The deepithelialized extended parascapular flap with large fascial extensions of dorsal thoracic fascia is our procedure of choice. This fascia can be folded into variable thicknesses to correct subtle contour defects of the upper lip, medial canthus, eyelids, and ear that have reportedly been difficult to reconstruct.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Salvage of traumatic below-knee amputation stumps utilizing the filet of foot free flap: critical evaluation of six cases.
Over a 12-year period between 1979 and 1991, 27 patients were operated on at the New York University Medical Center for salvage of below-knee amputation stumps utilizing free flaps. Six different donor sites were used. In 6 patients, the amputated foot was the donor site for a free flap to cover the tibial stump. There were 3 males and 3 females in this group. Five of the patients underwent immediate filet of foot reconstructions, while 1 patient had a reconstruction performed 69 days after injury, electively, when it was determined that below-knee amputation was the best option. All foot flaps survived and ultimately provided the major soft-tissue coverage for the below-knee amputation stump. The length of hospitalization ranged from 24 to 118 days. The time required from foot filet procedure to ambulation was 2, 4, 6, 7, 9, and 12 months in the 6 patients. Five of the 6 patients have resumed work or school after their injury. Foot flaps were based on the posterior tibial artery, anterior tibial artery, or both vessels. Nerve anastomosis of the posterior tibial nerve was performed in 5 patients. In 1 patient it was possible to maintain the continuity of the posterior tibial nerve. Five of the 6 patients were tested over a year after the flap, and all have good cold, pressure, and vibration sensation. Two of the 5 patients have heat sensation, and all 5 patients have at least protective pressure sensation. All the patients ambulate well with a below-knee prosthesis.
Adolescent↗
The fetal fibroblast: the effector cell of scarless fetal skin repair.
Human fetal skin heals without scar formation when it is transplanted to a subcutaneous location on an adult athymic mouse and subsequently wounded. In contrast, human fetal skin of identical gestational age heals with scar formation when transplanted to a cutaneous location on the athymic mouse recipient. To determine if mouse (adult) or human (fetal) fibroblasts are healing the graft wounds, we performed indirect immunohistochemistry for mouse and human collagen types I and III. Full-thickness skin grafts (n = 51) from human fetuses at 18 weeks' (n = 4) or 24 weeks' (n = 2) gestational age were placed onto athymic mice in two locations: cutaneously onto a fascial bed and subcutaneously in a pocket under the murine panniculus carnosus. Linear incisions were made in each graft 7 days after transplantation. Grafts were harvested at 7, 14, and 21 days after wounding and stained with hematoxylin and eosin or Mallory's trichrome. Immunohistochemistry for either human collagen type I or type III or for mouse collagen type I was performed. The subcutaneous grafts healed with human collagen types I and III in a scarless pattern. The wound collagen pattern was reticular and unrecognizable from the surrounding dermis. Hair follicles and sebaceous gland patterns were unchanged in the wounded dermis. Conversely, the cutaneous grafts healed with mouse collagen in a scar pattern with disorganized collagen fibers and no appendages. Mouse collagen scar was present along the base of the cutaneous grafts and as a thin capsule around the subcutaneous grafts. We conclude that (1) subcutaneous grafts heal with human fetal collagen and no scar formation, and (2) cutaneous grafts heal with mouse collagen in a scar pattern. Fetal fibroblasts can heal fetal skin wounds without scar despite being perfused by adult serum and inflammatory cells in an adult environment. These data suggest that the fetal fibroblast is the major effector cell for scarless fetal skin repair.
Animals↗
Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds.
The balance between matrix deposition and tissue turnover is fundamental in wound healing. It is likely that the balance between proteolytic enzymes and their inhibitors contributes to this balance. Matrix metalloproteinases are clearly important in tissue turnover, but their roles in wound healing are poorly understood. To investigate this, fluid from healing wounds resulting from mastectomies was collected from 1 h to 10 d post-surgery, and was analyzed for tissue inhibitor of metalloproteinases-1 concentrations. In all cases, tissue inhibitor of metalloproteinases-1 levels were initially comparable to those in serum, but increased rapidly to significantly higher levels within two days, with a tenfold average increase for five patients. On the other hand, zymography revealed that gelatinase A (72 kDa) levels increased moderately, whereas gelatinase B levels (92 kDa) decreased an average of twofold within 4 d. In contrast, fluid from chronic wounds had significantly more gelatinolytic activity, including lower-molecular-weight proteinase species that may represent activated or superactivated gelatinase fragments, as suggested by immunoprecipitation with specific antibodies. Tissue inhibitor of metalloproteinases-1 levels were lower in chronic than in healing wounds. These data may indicate that excess proteolysis in chronic wounds retards successful healing, and results from an imbalance of proteinase and inhibitors, as well as the presence of higher levels of activated metalloproteinases.
Chronic Disease↗
The in vivo effect of hyaluronan associated protein-collagen complex on wound repair.
Fetal skin wounds heal without scarring, however the underlying mechanisms remain unknown. Immunohistochemical staining and biochemical studies indicate the deposition of a collagen repair matrix that is highly organized. We have previously described a unique hyaluronan associated protein-collagen complex (HA-PC) profile present during the period of scarless healing in the sheep fetus. In this study, we examined the biologic activity of this HA-PC in an in vivo model of adult rat wound repair. A total of 84 incisional and 84 excisional wounds were examined by histology, TGF-beta immunocytochemistry and computer planimetry (excisional wounds only). Planimetry of the excisional wounds demonstrated the mean wound area remaining at day 1 was 88.7% for the control and 63.6% for the treated (p<0.01). At day 2, mean wound area was 81.5% for the control and 63.6% for the treated (p<0.01). At day 4, mean wound area was 56.6% for the control and 41.9% for the treated (p<0.01). At day 7, mean wound area was 26.9% for the control and 16.8% for the treated (p<0.01). At day 14, mean wound area was 7.9% for the control and 3.4% for the treated (p<0.05). Collagen organization was judged to be greater in the treated compared to control wounds, with a mean organization score of 2.3 vs. 1.9 (p=0.0596; Wilcoxon Signed Rank Sum Test). There were significantly more neutrophils at the wound margin of the treated compared to control wounds, 4.0 vs. 2.7 (p=0.038; Paired Two Tailed Student's t-Test). There was no difference in the number of microphages at the wound margin of the treated compared to control wounds, 6.15 vs. 6.0 (p>0.05). TGFbeta1 and beta2 staining was decreased whereas TGFbeta3 staining was increased in the HA-PC treated wounds. These results suggest that compared to control wounds HA-PC treated wounds heal more quickly, with more organized collagen, more neutrophils at the wound margin and increased TGFbeta3 expression. Furthermore, these data suggest that the manipulation of scarring in adult wounds is possible by the addition of proteins present in fetal skin.
Animals↗
The function of KGF in morphogenesis of epithelium and reepithelialization of wounds.
The function of keratinocyte growth factor (KGF) in normal and wounded skin was assessed by expression of a dominant-negative KGF receptor transgene in basal keratinocytes. The skin of transgenic mice was characterized by epidermal atrophy, abnormalities in the hair follicles, and dermal hyperthickening. Upon skin injury, inhibition of KGF receptor signaling reduced the proliferation rate of epidermal keratinocytes at the wound edge, resulting in substantially delayed reepithelialization of the wound.
Aging↗
Fetal fibroblast contraction of collagen matrices in vitro: the effects of epidermal growth factor and transforming growth factor-beta.
Wound contraction is an important component of healing but, in the extreme, may lead to excessive scar formation and pathological wound contracture. Fetal rabbit wounds heal without contraction or scarring, whereas excisional fetal sheep wounds have been shown to contract, but no scarring or pathological wound contracture is noted. We used an in vitro model, the fibroblast-populated collagen lattice, to study the ability of fetal fibroblasts to coordinate contraction of a collagen matrix and the modulating effects of epidermal growth factor and transforming growth factor-beta 1 on this contraction. With increasing gestational age, fibroblasts increased the degree of collagen lattice contraction. Epidermal growth factor inhibited contraction by fetal fibroblasts, whereas transforming growth factor-beta 1 stimulated it. These findings suggest that while intrinsic differences between fetal and adult fibroblasts exist, polypeptide growth factors may operate at the site of tissue repair to alter cell phenotype. Further work is underway to delineate the role of soluble protein factors responsible for the absence of scarring and contracture seen in the fetal wound.
Animals↗
Adult skin wounds in the fetal environment heal with scar formation.
OBJECTIVE: This study investigated the influence of the fetal environment on the healing characteristics of adult skin. SUMMARY BACKGROUND DATA: The remarkable ability of the fetus to heal without scarring is poorly understood. The unique qualities of fetal wound healing may be caused by the fetal environment, the fetal tissues, or a combination of both. There are numerous differences between the prenatal and postnatal environments that may play a role in the unique fetal response to injury. METHODS: Full-thickness adult sheep skin was transplanted onto the backs of 60-day-gestation fetal lambs (term, 145 days of gestation). The adult skin grafts were thus perfused by fetal blood and bathed in amniotic fluid. Previous work has demonstrated that, before midgestation, fetal lambs do not reject allogenic skin grafts. Forty days later (100 days of gestation), incisional wounds were made on both the adult skin graft and the adjacent fetal skin. The wounds were harvested 14 days postwounding and analyzed by both light microscopy and immunohistochemical testing using antibodies to collagen types I, III, and VI. RESULTS: The wounds in the adult skin grafts healed with scar formation. This observation contrasts strongly with the scarless healing of the incisional fetal skin wounds. CONCLUSIONS: This study suggests that scarless fetal skin healing properties are intrinsic to fetal skin and are not primarily the result of the fetal environment.
Amniotic Fluid↗