Faculty Bibliography

The process of bone lengthening by cortical fracture and gradual distraction of callus has become well established in the enchondral bones of the extremities. In this study the principles of bone lengthening were applied to the membranous bone of the craniofacial skeleton using the growing dog mandible as a model. Six mongrel dogs five months of age were studied. A unilateral, periosteal-preserving angular corticotomy was performed, and an external minilengthening device was fixed to the mandible perpendicular to the corticotomy. After 10 days of external fixation, the mandible was lengthened 1 mm/day for 20 days and then held in external fixation for 56 days (8 weeks) after which all dogs were killed. Anthropometric measurements and histological analysis of the specimens confirmed that bone lengthening had occurred and that new cortical bone was formed in the expanded areas

Human fetal surgery is being successfully performed today in a small number of highly selected patients for conditions that may lead to irreversible damage to the fetus and threaten the viability of the newborn. Following surgical repair, fetal wounds heal without scarring. This study was initiated to characterize fetal wounds both histologically and biochemically. Gore-Tex tubing was implanted into the subcutaneous tissue of the back of fetal, newborn, and adult New Zealand white rabbits. Light microscopic examination of healed wounds revealed no evidence of scar formation. Electron microscopy demonstrated a striated fibrillar structure suggestive of collagen within the lumen of the Gore-Tex tubing implants. Amino acid analysis (sensitivity 40 pmol) confirmed the presence of hydroxylysine and hydroxyproline within the Gore-Tex wound chambers indicating the presence of collagen in fetal wounds. The small amount of collagen precluded the typing of the collagen using cyanogen bromide peptide analysis. The absence of scarring and the small amounts of detectable collagen suggest a high degree of reorganization of the connective tissues involved in repair. The fetal wound matrix is rich in hyaluronic acid. Topical hyaluronic acid has been associated experimentally with a reduced amount of scarring in postnatal wound healing. Hyaluronic acid extracted from human skin and scar tissue is associated with collagen and other proteins. We propose that a hyaluronic acid-collagen-protein complex may play a role in fetal wound healing

Complications of microsuture repair of peripheral nerves include mechanical trauma, foreign body reaction, impairment of vascularity, and possible obstruction to successful sprouting. In addition, there are occasions when it is virtually impossible to perform a suture repair because of limited exposure and/or very fine structures, such as are encountered in pediatric cases. These situations have continued to provide the impetus for evaluating alternative methods of nerve coaptation. Recently, the use of tissue glue has gained in popularity as a technique for sutureless nerve repairs. We decided to test the efficacy of fibrin glue repair versus microsuture coaptation in the rat sciatic model. The repair sites were assessed for tensile strength, by quantitative morphometry, and by electrophysiologic studies. Tensile strength findings revealed that at two, four, and eight weeks after surgery, there was no significant difference between the two repair techniques, although there was a trend toward a stronger hold in the microsuture repairs. Electrophysiologic recordings revealed that conventional microsuture repairs had significantly faster conduction velocities, larger area under the curve, and higher peak amplitudes. The onset and peak latencies were comparable, revealing that the axonal quality of at least a certain number of axons was similar electrically. Axonal counts both proximal and distal to the repair showed no significant difference, although there was an overall suggestion of superiority in the number of myelinated axons in the suture repair

Recent clinical and experimental evidence suggests that the fetus responds to injury in a fashion fundamentally different from that of the adult. Our initial experience with human open fetal surgery reinforces experimental observations that the fetal wounds heal without the scarring, inflammation, and contraction that often accompany adult wounds. In this study we examine fetal wound fluid in an attempt to elucidate the control mechanisms that endow the fetus with unique healing properties. The extracellular matrix of fetal wounds is rich in hyaluronic acid, a glycosaminoglycan found in high concentrations whenever there is tissue proliferation, regeneration, and repair. We establish that wound fluid from the fetus contains high levels of hyaluronic acid-stimulating activity that may underlie the elevated deposition of hyaluronic acid in the fetal wound matrix. In contrast there was no hyaluronic acid-stimulating activity present in adult wound fluid. Hyaluronic acid, in turn, fosters an extracellular environment permissive for cell motility and proliferation that may account for the unique properties observed in fetal wound healing.

The sine qua non of malignancy is the ability of tumor cells to migrate and invade surrounding tissue. There are many substances that have been described that enhance cell motility and hyaluronic acid is prominent among these. Hyaluronic acid is a high molecular weight alternating disaccharide polymer found in abundance in extracellular matrices whenever rapid cell proliferation or tissue regeneration and repair occur. It creates a permissive environment for cell motility during embryogenesis, and high levels of hyaluronic acid also correlate with increased tumor cell invasion and aggressiveness. Little is known about the regulation of hyaluronic acid production, either in normal tissue or in malignancy. In this study, we characterize a hyaluronic acid-stimulating activity in fetal calf serum and describe a similar activity in the sera of breast cancer patients. The stimulating activity was measured by placing aliquots of test substance on fibrosarcoma cells. These indicator cells, which synthesize copious quantities of hyaluronic acid, respond to stimulation in a time- and dose-dependent fashion. The fetal calf serum hyaluronic acid-stimulating activity is maximum early in gestation and then falls rapidly to essentially no activity at term. This activity was partially purified from 120-day fetal calf serum by concanavalin A-Sepharose affinity and ion exchange chromatography and is accounted for by a glycoprotein with a molecular weight of 150,000 on gel filtration under native conditions. The sera of breast cancer patients with measurable burden of disease also contained hyaluronic acid-stimulating activity, which was not present in normal serum donors or in breast cancer patients without evidence of disease. The production of this stimulating activity may contribute to the development of the malignant phenotype by inducing hyaluronic acid-rich microenvironments that are permissive to tumor cell invasion and metastases.

Neurite promoting factors (NPF), fibroblast growth factor, and laminin were instilled inside autologous venous nerve conduits (AVNC) interposed across a 1 cm gap in the rat sciatic nerve. Axonal regeneration was measured electrophysiologically and histologically and was compared to control AVNC and autologous nerve grafts (ANG) in 45 rats. By 1 month, the AVNC group with NPF recovered an average nerve conduction velocity twice that of the ANG group (24 m/sec vs. 12 m/sec). The gastrocnemius muscle action potential of NPF grafts was twice that of the control AVNC and was similar to the ANG (1.63 mV vs. 0.87 mV). In subsequent months, the advantage of NPF disappeared; these grafts were grossly reduced to fibrous bands. Histological examination of these grafts at 5 months revealed a florid intraluminal fibrovascular proliferation, which appeared to be "choking off" the regenerating axons. It is suggested that more refined mixtures of NPF should be instilled inside AVNC so that the improved axonal regeneration is maintained while the late inhibitory fibrosis is avoided.