Adzick Ns

Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid.

Midgestation fetal wound healing is characterized by healing without fibrosis or scar formation. The mechanisms that underlie this remarkable process are mediated in part through a fetal wound extracellular matrix rich in hyaluronic acid. In this study a newly developed assay was used to determine the hyaluronic acid levels in fetal and adult wound fluid. Adult wound fluid had a rapid increase in hyaluronic acid, which peaked at 3 days and decreased to 0 by 7 days. In contrast levels of hyaluronic acid in fetal wound fluid increased rapidly and remained significantly elevated for 3 weeks. This prolonged presence of hyaluronic acid in the matrix of fetal wounds creates a permissive wound environment that promotes fetal fibroblast movement and proliferation and inhibits cytodifferentiation. Such a matrix environment promotes healing by regeneration rather than by scarring. This observation has therapeutic implications. The prolonged application of hyaluronic acid or hyaluronate protein complexes to wounds in children or adults may modulate healing in a manner that makes the wounds more fetal-Iike.

Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax

MOST infants with congenital diaphragmatic hernia die because their lungs are inadequate to support extrauterine life. This remains true despite advances in postnatal care, including preoperative stabilization,1 , 2 pharmacologic treatment of persistent pulmonary hypertension of the newborn,3 , 4 and temporary support with extracorporeal membrane oxygenation.5 , 6 Recently, prenatal diagnosis has allowed us to define the natural history of fetal diaphragmatic hernia better: approximately 75 percent of fetuses with congenital diaphragmatic hernia detected before birth die despite optimal postnatal care.7 8 9 10 11 The neonatal outcome is related to the degree of pulmonary hypoplasia from in utero lung compression, which is determined by the timing and volume .xa0.xa0.

Adult Skin Wounds in the Fetal Environment Heal with Scar Formation

ObjectiveThis study investigated the influence of the fetal environment on the healing characteristics of adult skin. Summary Background DataThe 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. MethodsFull-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 allogeneic 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. ResultsThe wounds in the adult skin grafts healed with scar formation. This observation contrasts strongly with the scarless healing of the incisional fetal skin wounds. ConclusionsThis study suggests that scarless fetal skin healing properties are intrinsic to fetal skin and are not primarily the result of the fetal environment.

Antenatal intervention for congenital cystic adenomatoid malformation

In 2 fetuses with congenital cystic adenomatoid malformation (CCAM) with hydrops, in-utero resection of the enlarged pulmonary lobe reduced mediastinal shift and allowed expansion of normal lung tissue in both cases. In case 1, the 27-week-gestation fetus died from severe hydrops after premature delivery. In case 2, fetal CCAM resection was completed at 23 weeks gestation. At 30 weeks a girl was delivered with no evidence of pulmonary hypoplasia. Fetal surgery can now be entertained for otherwise fatal space-occupying intrathoracic lesions.

Fetal wound healing. The ontogeny of scar formation in the non-human primate.

OBJECTIVEnThis study determined how scar formation develops in a non-human primate model of fetal skin repair.nnnSUMMARY BACKGROUND DATAnA transition from healing scarlessly to healing with scar formation characterizes skin repair in rat and sheep fetuses. New knowledge of the regulatory processes occurring in the fetal wound at the initial stages of scar formation may provide insights into the early mechanisms of scar formation.nnnMETHODSnFull-thickness wounds were made in fetal rhesus monkey lips from 75 through 114 days gestation (n = 6, term = 165 days). Wounds were harvested at 14 days postwounding and processed for histology (hematoxylin & eosin, Massons trichrome) as well as immunohistochemistry (human type I or type III collagen).nnnRESULTSnWounds healed with complete restoration of normal tissue architecture in the 75-day gestation fetus. However in the 85-100 day gestation fetuses, wounds healed with an absence of hair follicles and sebaceous glands, but the dermal collagen pattern remained reticular and similar to that in unwounded dermis. At 107 days, a thin scar was present in the wound, thereby demonstrating a transition to scar formation between 100 and 107 days gestation (early 3rd trimester) in the non-human primate.nnnCONCLUSIONSnIn the non-human primate fetus, a transition from scarless repair to adult-type repair with scar formation occurs in the early third trimester. These data provide insight into the transition process; the ontogeny of scar formation is characterized initially by wounds healing without the presence of epidermal appendages but with a normal reticular dermal collagen pattern, which we term the transition wound.

Scarless fetal healing. Therapeutic implications.

The purpose of this report is to call attention to the fetal wound healing process as a blueprint for ideal tissue repair. Wound healing in the fetus is fundamentally different from healing in the adult. Fetal tissue repair occurs rapidly and in the absence of scar formation. Because scarring and fibrosis dominate some diseases in every area of medicine, an understanding of fetal wound healing should help develop therapeutic strategies to avert the devastating consequences of excessive scar formation.

Tracheobronchial obstructions in infants and children. Experience with 45 cases.

Forty-five infants and children with intrathoracic tracheobronchial obstructions requiring surgical treatment are reported. Segmental stenosis of the trachea is defined as involvement of less than one half the length of the airway, which affected six infants. Elongated stenosis involving more than one half the length of the trachea was seen in 12 infants, and complete annular cartilage rings, along the entire length of the trachea, were present in 11. Severe tracheomalacia occurred in six infants associated with aortic arch anomalies and in nine infants with esophageal atresia. Segmental tracheal resection was performed in 17 cases (two after failure of a rib cartilage graft), and anastomotic stricture developed in three. These three anastomotic strictures were resected, resulting in an excellent airway in two and restricture in one. Rib cartilage grafts were used in five patients: two of three with elongated stenosis with complete tracheal rings required subsequent resection, and one of two infants with tracheomalacia had excellent outcome. Approximately 50% of an infants trachea can be resected, but rib cartilage grafts should be used for elongated stenosis. Resection of bronchial stenosis in two patients resulted in a widely patent bronchus. From this experience primary segmental tracheobronchial resection and re-resection of recurrent stenosis are highly successful. Anastomotic stricture is due to tension at the suture line and suture material inciting a fibrotic reaction. Rib cartilage grafts amounting to 25% or less of the circumference of the airway readily resurfaces with adjacent epithelium, but when 30% or more of the circumference is rib graft, epithelialization may be impaired.

Fetal diaphragmatic wounds heal with scar formation

Fetal wound healing is fundamentally different from wound healing in the adult. Although experimental work in mice, rats, rabbits, monkeys, and sheep has demonstrated that fetal healing occurs without inflammation and scarring, all of these studies have been limited to fetal skin wounds. Whether all fetal tissues heal in a regenerative-like fashion is unknown. Amniotic fluid exposure may play an important role in scarless fetal skin wound healing, but the effect of amniotic fluid on fetal mesothelial wound healing has not been characterized. To investigate these questions we created bilateral linear diaphragmatic wounds in 100-day gestation fetal lambs (term = 145 days). The right thoracotomy was closed to exclude amniotic fluid. In contrast, the left thoracotomy was fashioned into an Eloesser flap which permitted the left diaphragmatic wound to be continually bathed in amniotic fluid. Wounds were harvested after 1, 2, 7, or 14 days and analyzed by light microscopy and immunohistochemistry with antibodies to collagen types I, III, IV, and VI. Whether bathed in or excluded from amniotic fluid, the mesothelial-lined diaphragm healed with scar formation and without evidence of muscle regeneration. Interestingly, diaphragmatic wounds exposed to amniotic fluid were covered by a thick fibrous collagen peel similar to that seen in gastroschisis bowel. These findings indicate that not all fetal tissues share the unique scarless healing properties of fetal skin.

Fetal fracture healing in a lamb model.

A large animal model to assess fetal fracture repair and the ability to close excisional bony defects is presented. Incisional and excisional ulnar fractures were made in 14 midgestation fetal lambs, harvested at serial time points, and subjected to high-resolution low-kilovolt magnification radiographs, magnetic resonance imaging scans, and histologic analysis. Fetal fracture healing was characterized by early closure of excisional defects and rapid fracture healing with minimal or no soft-tissue inflammation or callus formation. Magnetic resonance imaging scans of the fractures revealed a characteristic pattern compatible with the histologic findings, namely, minimal inflammation in soft tissue adjacent to the fracture site. Histologic and magnification radiographic findings indicated that complete bony repair occurred within 21 days in incisional defects and within 40 days in excisional defects. In both cases, healed fetal bone resembled normal bone matrix. Excisional defects, including periosteum, of greater than three times the width of the bony cortex closed rapidly with virtually normal-appearing bony matrix and with minimal or no callus formation.

Delayed in utero repair of surgically created fetal cleft lip and palate.

&NA; To properly evaluate the potential benefits of in utero repair for cleft lip and palate, an animal model of cleft lip and palate formation is needed that simulates human cleft morphology. We have developed a fetal lamb model in which incisional or excisional unilateral cleft lips were created early in gestation and later repaired. Through a maternal celiotomy and hysterotomy, six excisional and six incisional clefts were created in early first trimester fetal lambs. Clefts were created by a novel “space helmet” technique and made completely through the lip and the alveolus. Two weeks later, the wound edges were freshened and repaired in all but one lamb in each group. In the early third trimester, the fetuses were harvested and studied. We found that the incisional clefts healed spontaneously with replacement of the native reticular collagen pattern and with regeneration of the skin appendages. However, the excisional clefts did not autorepair and, when repaired surgically, healed without a collagen scar but showed no regeneration of the skin appendages. This preliminary study is the first successful large animal model where cleft lips and palates were created, allowed to develop with the cleft, and later repaired in utero. Prior to repair, the edges of the excisional clefts epithelialize. When repaired early in the third trimester, excisional clefts heal without a dermal scar but exhibit incomplete regeneration of the skin appendages. (Plast. Reconstr. Surg. 97: 900, 1996.)