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1993-07-02-05 Fetal plastic surgery: a review and preview © Chang www.thefetus.net/


Fetal plastic surgery: a review and preview

James Chang, BAS, H. Peter Lorenz, MD, Michael R. Harrison, MD, Michael T. Longaker, MD

Address correspondence to: Michael T. Longaker, MD., Institute for Reconstructive Plastic Surgery, New York University, Medical Center, 550 First Ave., New York, NY 10016-6451. Ph: 212-263-5207; Fax: 212-263-5400. All other authors: S343, Dept. of Surgery, Box 0470, UCSF Medical Center, San Francisco, CA 94143-0470. Ph: 415- 476-1239 Fax: 415-476-1734

MESH Surgery, Plastic; Fetus physiology, -surgery; Cleft-lip surgery. ICD9 75 CDC 75.360

Introduction

Plastic surgery on the human fetus seems implausible, but with recent advances in fetal surgery and the phenomenon of scarless fetal wound healing, it may one day become a possibility. Imagine correcting craniofacial anomalies and other congenital deformities in utero, thereby preventing abnormal tissue growth and disfigurement while leaving no evidence of the operation. In this review, we wish to outline the development of human fetal surgery, to introduce preliminary laboratory investigations into scarless fetal repair along with animal models of in utero plastic surgery and, finally, to consider implications for its future application in specific congenital anomalies in humans.

History

The past decade has witnessed the introduction and development of human fetal surgery1.  At the Fetal Treatment Center of the University of California, San Francisco, life-threatening malformations such as congenital diaphragmatic hernia, obstructive uropathy, and cystic adenomatoid malformation of the lung have been prenatally diagnosed by ultrasound. Using specialized instruments and monitoring techniques, surgeons have been able to correct these malformations in highly selected patients in utero. The success of these extremely intricate procedures remains limited by the problems of peri- and postoperative premature labor and adequate postoperative intensive care management of both mother and fetus2. Fetal surgeons have already made great advances from their early experience.

Scarless fetal skin wound healing

One of the most exciting developments from the human fetal surgery enterprise has been the study of scarless fetal skin wound healing. Unlike adult tissue, fetal dermal repair seems to occur in a fundamentally different way, resulting in scarless wound healing3. Fetal skin heals without macroscopic evidence of prior injury, and the dermis reveals a highly organized collagen architecture. This phenomenon of scarless fetal skin repair has been observed in mice, rats, rabbits, monkeys (fig. 1-3), opossum, and humans4. Nevertheless, much of this work has been accomplished in the sheep model because of the animal"s prolonged gestation time, ease of fetal exposure and manipulation, and a relative resistance to premature labor. In fetal lambs, incisional wounds heal without scarring at 100 days" gestation and begin to scar at 120 days; gestation (term pregnancy=145 days) 5. Therefore, a transition period exists during which the fetus begins to heal in the usual adult-like manner. Using the fetal rhesus monkey model, we have determined that an intermediate "transition" wound occurs whereby the wound heals with a normal collagen pattern but without restoration of normal hair follicle and sweat gland patterns6.

Figure 1: Intraoperative photograph of a 75 day gestation (term=165 days) fetal rhesus monkey, with a 2 mm excisional wound (arrow) made in the upper lip, which was approximated with sutures.

Figure 2: Same fetus as in fig. 1, after wounding. The lip wound is not grossly visible, except for its sutures (arrows). This wound healed without scar formation.

Figure 3: Immunohisto-chemical staining for collagen type III in an identical gestational age monkey lip wound (arrow), demonstrates scarless fetal wound repair in the non-human primate. The wound collagen pattern is reticular and indistinguishable from that of collagen in the surrounding unwounded dermis. The sebaceous gland and hair follicle patterns are unchanged in the scarless wound (50x). (Reprinted with permission from ref. 6.)

Differences between fetal and adult wound healing

Researchers are beginning to examine the differences between fetal and adult wound healing (Table 1).

Table 1: Differences between fetal and adult healing.

g Intrauterine environment: amniotic fluid rich in:
1
growth factors
1
hyaluronic acid
1
fibronectin

g Intrauterine environment: amniotic fluid  poor in:
1
oxygen (pO2 is roughly 3-4 times less than in adults).

g minimal acute inflammatory response

g paucity of neutrophils

g macrophages recruited to fetal wound

g high level of hyaluronic acid

g enhanced fibronectin production

These differences include those involving the intrauterine environment where the fetus is bathed in amniotic fluid rich in growth factors, hyaluronic acid, and fibronectin, and where the fetus remains relatively hypoxic. Mid-gestational fetal lamb tissue pO2 is roughly 16 mmHg, whereas adult tissue pO2 ranges from 45 to 60 mmHg3 .

Intrinsic differences also exist between fetal and adult tissue. Notably, in fetuses, there is a minimal acute inflammatory response with a paucity of neutrophils3. In addition, recent data from our research group suggests that macrophages are recruited to fetal wounds and express several types of growth factors (transforming growth factor, tumor necrosis factor) which may regulate tissue repair7). It appears that fetal wound healing utilizes different and perhaps more selective cellular mechanisms of tissue repair. Other considerations in fetal versus adult tissue repair include a fetal wound matrix rich in hyaluronic acid (a major glycosaminoglycan that facilitates cell migration), the explosive growth and synthetic potential of fetal fibroblasts with organized collagen deposition, and enhanced fibronectin production during embryogenesis3.

Much of our laboratory work focuses on understanding the mechanisms regulating fetal repair in order to eventually manipulate adult wounds to heal without scarring. However, we are also interested in exploring the possibility of in utero surgery for craniofacial anomalies and other congenital lesions. By taking advantage of the unique wound healing ability of the fetus, surgeons may be able to provide optimal, definitive repair of congenital anomalies.

Selection criteria

Certainly before any elective surgery on non-life-threatening defects could be performed on humans, a strict criteria of guidelines must be established. The congenital anomaly must be unequivocally diagnosed in utero by ultrasound, and the lesion must be of a nature that would cause significant morbidity and/or psychological distress with current postnatal operations. The anatomic pathology and operative techniques must be well-established in a rigorous animal model. Most importantly, risk to the mother and fetus must be absolutely minimal2.

Animal models

Several animal models of fetal plastic surgery have been established to investigate these issues. To date, almost all animal models have involved the creation and repair of cleft lips, which are technically the easiest fetal congenital lesion to repair. In 1985, Hallock played a pioneering role in this new field by describing a fetal cleft lip model in mice, where Dilantin- induced lip clefts were successfully repaired on day 17 of the usual 19-day gestation8. His further work has involved repairing a surgically divided lip in the fetal rhesus monkey9. We have previously established a cleft lip model in fetal rabbits10. As expected, the fetal rabbits healed without histologic evidence of scarring. More importantly, cephalometric measurements after successful lip repair in these rabbits exhibited normal maxillary length and width11-13. These data supported the hypothesis that scarless repair would allow subsequent normal facial growth.

The sheep model has provided valuable information regarding in utero repair of cleft lips. Longaker and colleagues recently reported a fetal cleft lip repair model in lambs, also documenting scarless healing of the cleft lip without secondary mid-face growth retardation14. The most exciting innovation, however, has been the use of endoscopic technology. Estes and colleagues were able to create and repair a cleft lip in fetal lambs using small endoscopic ports rather than the conventional large hysterotomy incision. The authors suggested that these small incisions may allow for surgical repair earlier in gestation and may prevent the postoperative difficulties with preterm labor that have hindered human fetal surgery thus far15.

Potentially treatable lesions

Having discussed human fetal surgery, laboratory observations of scarless fetal wound healing, and the various animal models established, which craniofacial anomalies and congenital deformities would be candidates for in utero repair in the future (Table 2) ?

Table 2: Potentially treatable lesions.

g cleft lip

g cleft palate

g craniofacial clefts

1 Treacher-Collins syndrome

g craniofacial microsomia

g craniosynostosis with resultant skull deformities

g hyper- and hypotelorism

g Pierre-Robin syndrome

g syndactyly

g amniotic band syndromes

Cleft lip is the most likely lesion to be repaired in utero because the operation would be technically least difficult. Other more complicated craniofacial anomalies which could be prenatally diagnosed by ultrasound include: cleft palate; centric and acentric craniofacial clefts, including Treacher-Collins syndrome; craniofacial microsomia; craniosynostosis with resultant skull deformities; orbital hypertelorism and hypotelorism; and Pierre-Robin syndrome. Aside from craniofacial defects, syndactyly and amniotic band syndromes are other congenital lesions that would be potential candidates for in utero repair16,17,18. All of these complicated defects will require the development of reliable animal models prior to considering prenatal repair. By studying the natural history and developmental pathophysiology of these resultant defects, surgeons will learn when to best intervene. Furthermore, the operations for these more complicated defects may prove to be extremely demanding relative to correcting cleft lips in utero and may require substantial training before they can be performed on humans.

Rationale for fetal surgery

All conventional postnatal plastic surgery falls short of truly optimal repair— either due to the remaining functional deficit or subsequent scarring. Based on the animal models described above, it is clear that correctly timed fetal repair of surgically created cleft lips results in normal aesthetic facial morphology. Therefore, the rationale for operating in utero would be to intervene at an early stage of development, preventing the devastating developmental sequelae evident at birth, and to allow fetal wound healing capabilities to optimize tissue repair. While some critics argue that fetal plastic surgery would be too costly, one must take into account the considerable time and expense involved in conventional postnatal craniofacial surgery. For example, reconstructive surgery for young patients with Treacher-Collins syndrome or even cleft palate may require multiple operations as well as years of orthodontic and speech therapy.

Future development

What lies in the future for fetal plastic surgery? We certainly do not advocate plastic surgery on the fetus at this point, but instead offer a preview of a field that may one day develop.

Limits

At the present time, fetal plastic surgery is limited by several issues. First of all, surgeons must continue to develop safe operative techniques for fetuses with life-threatening malformations. Obviously, until such operations are routinely successful, it is much too early to attempt human fetal surgery for non-life-threatening malformations such as cleft lip or craniosynostosis. While much of the experimental work to date has focused on cleft lip, considerably more experience in animal models is necessary to determine which other congenital anomalies may also be treated by fetal surgery. The development of fetal wound healing has offered plastic surgeons the possibility for scarless repair. We continue to advocate caution in this field19 but, at the same time, hope that scientists will further provide both molecular answers and animal models for this fascinating phenomenon.

References

1. Harrison MR, Adzick NS, Longaker MT, et al : Repair of a congenital diaphragmatic hernia in utero. N Engl J Med 322: 1582-1584, 1990.

2. Longaker MT, Golbus MS, Filly RA, et al: Maternal outcome with open fetal surgery: Analysis of the first 17 cases. JAMA 265: 737-741, 1991.

3. Longaker MT, Adzick NS: The biology of fetal wound healing: A review. Plast Reconstr Surg 87: 788-798, 1991.

4. Adzick NS, Longaker MT: Animal models for the study of tissue repair. J Surg Res 51: 216-222, 1991.

5. Longaker MT, Whitby DJ, Adzick NS, et al: Studies in fetal wound healing, VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation. J Pediatr Surg 25: 63-69, 1990.

6. Lorenz HP, Whitby DJ, Longaker MT, Adzick N S.: Fetal wound healing: The ontogeny of scar formation in the nonhuman primate. Ann Surg 217:391-6, 1993.

7. Longaker MT, Bouhana KS, Roberts AB, Harrison MR, Adzick NS, Banda MJ: Regulation of fetal wound healing. Surg Forum 42: 654-655, 1991.

8. Hallock GG. In utero cleft lip repair in A/J mice. Plast Reconstr Surg. 75: 785-790, 1985.

9. Hallock GG, Rice DC, McClure HM. In utero lip repair in the rhesus monkey: an update. Plast Reconstr Surg 80: 855-858, 1987.

10. Longaker MT, Dodson TB, Kaban LB: A rabbit model for fetal cleft lip repair. J Oral Maxillofac Surg 48: 714-719, 1990.

11. Dodson TB, Schmidt B, Longaker MT, et al: Fetal cleft lip repair in rabbits: postnatal facial growth after repair. J Oral Maxillofac Surg 49:603-611, 1991.

12. Kaban LB, Longaker MT, Stern M, et al: Wound healing and facial growth after fetal cleft lip and palate repair. Oral Maxillofac Surg Clin North Am 3: 735-746, 1991.

13. Kaban LB, Dodson TB, Longaker MT, et al: Fetal cleft lip repair in rabbits: Long term clinical and cephalometric results. Cleft Palate Craniofacial J 30:13-21, 1993.

14. Longaker MT, Stern M, Lorenz HP, et al: A model for fetal cleft lip repair in lambs. Plast Reconstr Surg 90:750-756, 1992.

15. Estes JM, Whitby DJ, Lorenz HP, et al: Endoscopic creation and repair of fetal cleft lip. Plast Reconstr Surg 90:743-746, 1992.

16. Whitaker LA, Bartlett SP: Craniofacial anomalies. In Jurkiewicz MJ, Krizek TJ, Mathes SJ, and Ariyan S, (eds): Plastic Surgery: Principles and Practice, C.V. Mosby Company, St. Louis, 1990.

17. Longaker MT, Harrison MR, Kaban LB: Concepts of fetal surgery: Application in craniofacial anomalies. In Kaban L B, (ed): Pediatric Oral and Maxillofacial Surgery, W.B. Saunders Company, Philadelphia, 1990.

18. Longaker MT, Kaban LB: Fetal models for craniofacial surgery: Cleft lip/palate and craniosynostosis. In Adzick NS Longaker MT, (eds): Fetal Wound Healing, Elsevier, New York, 1992.

19. Longaker MT, Whitby DJ, Adzick NS, et al: Fetal surgery for cleft lip: A plea for caution. Plast Reconstr Surg 88:1087, 1991.

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