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Biomedical subjects

Daniel A Hunter

Publications and source records attributed to Daniel A Hunter.

At least 19 recordsLinked to original sources
PubMed2006

Repair of motor nerve gaps with sensory nerve inhibits regeneration in rats.

OBJECTIVE: Sensory nerve grafts are often used to reconstruct injured motor nerves, but the consequences of such motor/sensory mismatches are not well studied. Sensory nerves have more diverse fiber distributions than motor nerves and may possess phenotypically distinct Schwann cells. Putative differences in Schwann cell characteristics and pathway architecture may negatively affect the regeneration of motor neurons down sensory pathways. We hypothesized that sensory grafts impair motor target reinnervation, thereby contributing to suboptimal outcomes. This study investigated the effect of motor versus sensory grafts on nerve regeneration and functional recovery. STUDY DESIGN: The authors conducted a prospective, randomized, controlled animal study. METHODS: Fifty-six Lewis rats were randomized to seven groups of eight animals each. Five-millimeter tibial nerve defects were reconstructed with motor or sensory nerve grafts comprised of single, double, triple, or quadruple cables. Tibial nerve autografts served as positive controls. Three weeks after reconstruction, nerves were harvested for histologic examination and quantitative histomorphometric analysis. Wet muscle masses provided an index of functional recovery. RESULTS: Nerve regeneration was significantly greater across motor versus sensory nerve grafts independent of graft cross-sectional area or cable number. Motor grafts demonstrated increased nerve density, percent nerve, and total fiber number (P < .05). Normalized wet muscle masses trended toward improved recovery in motor versus sensory groups. CONCLUSIONS: Reconstruction of tibial nerve defects with nerve grafts of motor versus sensory origin enhanced nerve regeneration independent of cable number in a rodent model. Preferential nerve regeneration through motor nerve grafts may also promote functional recovery with potential implications for clinical nerve reconstruction.

Analysis of Variance↗
PubMed2006

The effects of cavernous nerve grafting following surgically induced loss of erectile function in a large-animal model.

BACKGROUND: Prostate cancer is the second most common cause of cancer deaths in men in the United States. Many patients experience partial or complete loss of erectile function following prostatectomy. The cavernous nerves can be reconstructed intraoperatively using sural nerve grafts in an attempt to restore erectile function. METHODS: In this study, multiple anatomical dissections and neurologic assessments were used to define the position and histologic parameters of the cavernous nerve in a canine model. The subsequent experimental design included three groups of adult mongrel dogs followed for an 8-month period. Group 1, the control group, underwent bilateral nerve ablation to substantiate surgically induced loss of erectile function. Group 2, the "sham" group, underwent exploration only. Group 3 underwent bilateral cavernous nerve ablation with bilateral sural nerve graft reconstruction. Erectile function was evaluated with indirect electrical nerve and manual penile stimulation preoperatively and 1, 2, 4, 6, and 8 months postoperatively. Direct nerve stimulation and histologic analysis was preformed at the first operation and at the time the animals were euthanized at 8 months. RESULTS: Bilateral cavernous nerve ablation resulted in a significant loss of erectile function for 8 months postoperatively in the control animals. The sham animals demonstrated preservation of erectile function immediately following exploration. The animals in the grafted group demonstrated a significant return of erectile function by 4 months compared with preoperative measurements and by 2 months compared with control animals. CONCLUSIONS: This study establishes the first large-animal model for surgically induced loss of erectile function with successful cavernous nerve graft reconstruction, and it provides the unique opportunity to explore the effects of changes to this model in the future.

Animals↗
PubMed2006

Neuroregenerative effects of preinjury FK-506 administration.

BACKGROUND: FK-506 is used in organ transplantation because it promotes neurite outgrowth in vitro and enhances neuroregeneration in peripheral nerve injury transection models. Immunosuppressive mechanisms of FK-506 are well defined, with demonstration of decreased neuroregenerative effects with delayed administration. The purpose of this study was to describe the effects of preinjury administration of FK-506 in rats with tibial nerve transection injury. METHODS: Eight inbred male Lewis rats per group in three separate groups underwent tibial nerve transection with primary repair. Group I received placebo, group II received FK-506 treatment at 1 day before surgery, and group III received FK-506 preloading 3 days before surgery. RESULTS: Histologic and histomorphometric results demonstrated the preload FK-506 group had superior results compared with the immediate FK-506 group. Both FK-506 groups were superior to the placebo group. The preload FK-506 demonstrated superior regeneration in mean total nerve fiber counts (p < 0.05), greater percentage neural tissue (p < 0.05), greater mean nerve fiber density (p < 0.05), and lower percentage of debris (p > 0.05). Mean nerve fiber widths were similar in the preload and immediate FK-506 groups but superior to the placebo group. CONCLUSION: These data suggest that enhancement of FK-506's neuroregenerative effect is enhanced when administered before nerve injury such as when performing elective surgery.

Animals↗
PubMed2006

Influence of aging on regeneration in end-to-side neurorrhaphy.

Aging profoundly affects the structural and functional characteristics of the peripheral nervous system. Although several experiments have investigated the effect of aging on nerve regeneration after crush and transection nerve injuries, little is known about the influence of age on end-to-side nerve repairs. It was hypothesized that decreased terminal and collateral sprouting in older animals would be associated with less robust regeneration through end-to-side nerve repairs. In this study, 27 Lewis rats underwent end-to-side repair at ages 2 weeks, 3 months, or 1 year. Histomorphometric assessments at 12 weeks demonstrated increased fiber width, percent neural tissue, and neural density in animals undergoing nerve reconstruction at the age of 2 weeks (P < 0.05). A trend toward further decline in regeneration was noted at ages 1 year versus 3 months. After end-to-side nerve repair, younger animals exhibit a more robust regenerative response, consistent with prior experience in other nerve injury models.

Aging↗
PubMed2006

Temporal factors in peripheral nerve reconstruction with suture scaffolds: an experimental study in rodents.

PURPOSE: This study investigated nerve regeneration following nerve repair with longitudinally oriented sutures, with emphasis on timing. Prior work in rodents has shown that suture scaffolds are comparable to nerve grafting when assessments are made at late time points. However, rodents have exceptional regenerative capacity, making it difficult to detect key differences at late time points. This study therefore investigated regeneration across suture scaffolds both at early (4 week) and late (12 week) endpoints. METHODS: Rodents were randomized to nerve gap, transection and repair, nerve grafting, and suture scaffold groups. Nerve regeneration was evaluated at 4 and 12 weeks. Histomorphometry parameters were evaluated using binary image analysis of toluidine blue-stained nerve cross sections. RESULTS: Compared to nerve grafts, suture scaffolds were associated with significantly decreased neural density (4208 +/- 3546 vs. 193 +/- 416, fibers/mm;2, p<0.05) and fiber width (1.92 +/- 1.21 vs. 0.75+/- 1.16, microm, p<0.05). At 12 weeks, differences between groups were no longer detectable. CONCLUSION: When evaluated at optimal time points for rodents, suture scaffolds fail to support regeneration comparable to the existing gold standard of nerve grafting. This finding raises significant concerns regarding the clinical application of suture scaffolds.

Analysis of Variance↗
PubMed2005

Effects of Schwann cells and donor antigen on long-nerve allograft regeneration.

Nerve allotransplantation has been used successfully in human subjects to restore function after traumatic nerve injury and avoid subsequent limb amputation. However, due to the morbidity associated with nonspecific immunosuppression, this reconstructive approach has been limited to patients with particularly severe nerve injuries. It would be desirable to broaden the indications for such procedures through development of less toxic antirejection therapies. A miniature swine model of nerve transplantation was used to investigate the effects of preoperative ultraviolet-B (UV-B)-irradiated donor alloantigen portal venous infusion and injection of cultured major histocompatibility complex (MHC)-matched Schwann cells into the nerve graft. The transplanted ulnar nerves were harvested at 20 weeks. Histomorphometry showed marked enhancement in nerve regeneration through allografts injected with Schwann cells. Serial mixed lymphocyte assays demonstrated suppression of the recipient immune response to the donor antigen after pretreatment, but no additional neuroregenerative effect of donor alloantigen pretreatment.

Animals↗
PubMed2005

Schwann-cell injection of cold-preserved nerve allografts.

This study investigated the effects of prolonged cold preservation and Schwann-cell injection on nerve regeneration through peripheral nerve allografts. Forty rats were randomized to the following groups: group I, isograft; group II, allograft; group III, isograft + Schwann cells; group IV, 6-week cold-preserved allograft; and group V, 6-week cold-preserved allograft with Schwann cells. Nerves from all animals were harvested at 4 weeks after surgery for histological and histomorphometric analysis. Untreated allograft recipients demonstrated poor nerve regeneration and histological evidence of rejection. The remaining four groups showed robust regeneration without evidence of rejection. In a short nerve allograft model, prolonged cold preservation of allografts supported robust nerve regeneration, but the addition of cultured Schwann cells conferred no additional benefit for nerve regeneration. Further work in large animals is needed to establish the role for exogenous Schwann cells in nerve allotransplantation.

Animals↗
PubMed2005

Prolonged cold-preservation of nerve allografts.

The goal of this study was to determine the effect of varying durations of cold-preservation on the immunogenicity of nerve allografts and their subsequent ability to facilitate neuroregeneration across a short nerve gap. Allografts preserved for 1, 4, and 7 weeks were compared to untreated allografts and isografts. There was a shift from an interferon-gamma-producing cellular response (untreated allografts) to an absence of response (7-week cold-preserved allografts and isografts). There were no detectable alloantibodies by flow cytometry. Histomorphometry distal to the graft showed robust regeneration in the isograft and 7-week cold-preserved groups when compared to the untreated allograft group. Increasing duration of cold-preservation diminished the cellular immune response. This cold-preservation does not preclude subsequent nerve regeneration across a short nerve graft. Prolonged cold-preservation of nerve allograft tissue could serve as a means to produce unlimited graft material for use in peripheral nerve reconstruction.

Animals↗
PubMed2005

Regeneration through nerve isografts is independent of nerve geometry.

Investigators have theorized that tortuosity in nerve grafts may adversely affect nerve regeneration. This study investigated the effect of graft configuration and redundancy on regeneration across 2.5-cm rat sciatic nerve isografts. Thirty-two Lewis rats were randomized to four nerve grafting groups defined by gap distance and isograft conformation. In Group 1, grafts were interposed into a 2-cm gap, resulting in mild graft redundancy. In Groups 2 and 3, grafts were tacked in sinusoidal or omega-shaped configurations, respectively, to bridge a 0.5-cm gap. In Group 4, grafts were interposed after 1 cm of native sciatic nerve was resected, resulting in no graft redundancy and an interstump distance of 2.5 cm. At 6 weeks, nerve tissue was harvested; subsequent histomorphometric analysis revealed no significant differences in regeneration between groups. These data suggest that regeneration through isografts is independent of the graft geometry and redundancy.

Animals↗
PubMed2005

Effects of irradiation on nerve graft vasculature.

Increasing doses of therapeutic irradiation are known to impair nerve regeneration after grafting. One possible factor is the effect of irradiation on the endoneurial vasculature. This study investigates the effects of postoperative irradiation on the size, number, and cross-sectional area of endoneurial vessels in the rat posterior tibial nerve graft model. Sixty-five Sprague-Dawley rats underwent 1.5-cm interposition grafts to the tibial nerve. Postoperatively, they were assigned to one of five groups. The animals in Group 1 were unirradiated controls. Groups 2 to 5 received postoperative irradiation in the amounts of 46, 66, 86, and 106 Gy, respectively. One hundred and twenty days after grafting, sections of the proximal, grafted, and distal nerve were harvested and analyzed with digital morphometry. Statistical analysis of the average vessel area, number of vessels, and total vascular area was performed. The grafted segments of Groups 4 and 5 and the distal segments of all irradiated groups showed a statistically significant decrease in the number of vessels, compared to controls. The average size of the vessel was smaller in the proximal segment of the irradiated groups, compared to controls. There was no difference in size in either the grafted or distal segments of the irradiated groups, compared to controls. The observed changes in the endoneurial vasculature resulted from both the action of regeneration and the effects of irradiation. The irradiation effects appear to be dose-dependent.

Animals↗
PubMed2005

Assessment of the immune response to dose of nerve allografts.

Nerve allotransplantation provides a limitless source of nerve graft material for the reconstruction of large neural defects. It does require systemic immunosuppression or induction of immune unresponsiveness to prevent allograft rejection. It is unknown whether a greater volume of nerve graft material will increase the risk of rejection or the need for more intensive immunosuppression. This study assessed the relationship between the quantity of nerve tissue transplanted and the magnitude of the resulting immune response. Forty female (BALB/c) mice were randomly assigned to two groups that received either nerve isografts (BALB/c) or nerve allografts (C57BL/6). Each group was then subdivided into two groups that received either one or 10 sciatic nerve graft inlays. Histological and immunological assessments were performed at 10 days after engraftment. Histologic analysis demonstrated greater cellular infiltration in the allograft than the isograft groups but no appreciable difference in infiltration related to quantity of transplanted nerve tissue. In vitro assessments of the immune response using mixed lymphocyte assays and limiting dilution analysis similarly demonstrated a robust immune response to allografts but no effect on quantity of transplanted nerve tissue. These data suggest that larger peripheral nerve allografts may not be subject to increased risk for rejection.

Animals↗
PubMed2005

Analysis of the nerve branches to the orbicularis oculi muscle of the lower eyelid in fresh cadavers.

BACKGROUND: Scleral show or ectropion is a known complication of lower eyelid surgery. It is particularly problematic after lower eyelid blepharoplasty when the orbicularis oculi muscle is transected or after other procedures are performed that denervate the lower eyelid. The purpose of this study was to determine whether a dominant motor branch exists to the lower lid orbicularis oculi muscle, using anatomic dissection and histologic analysis. METHODS: Sixteen fresh facial cadaver halves were dissected using the operative microscope to identify and measure nerve branches. The nerves were then harvested, sectioned, and stained with toluidine blue dye for histomorphometric analysis. Nerves were categorized as either lateral or medial to a vertical line marked at the lateral edge of the limbus of the eye. RESULTS: Eighty-seven percent and 47 percent of cadaver halves had one and two nerve branches lateral to the limbus, respectively. Eighty percent and 47 percent of cadaver halves had one and two nerve branches medial to the lateral limbus, respectively. The nerve branches entered the inferior edge of the orbicularis oculi muscle between 0.88 cm (+/-0.36 cm) and 2.73 cm (+/-0.46 cm) from the lateral canthus. There was no correlation noted between fascicular counts and distance from the lateral canthus. CONCLUSIONS: Multiple motor nerves exist to the lower eyelid. Branches are found medial and lateral to the lateral limbus, and no nerve branch is dominant.

Blepharoplasty↗
PubMed2005

Effect of FK506 on peripheral nerve regeneration through long grafts in inbred swine.

Numerous small-animal studies have demonstrated that FK506 enhances nerve regeneration and accelerates functional recovery after nerve injury. However, no experimental study has corroborated these neuroregenerative effects in larger animals. This study investigated the effects of FK506 on nerve regeneration in inbred miniature swine. Eight animals received 8-cm ulnar nerve autografts and allografts. Treated animals received 0.1 to 0.4 mg/kg FK506 injections twice weekly to maintain immunosuppressive serum FK506 levels. At 24 weeks posttransplant, nerve grafts were harvested for histomorphometric analysis. Mixed lymphocyte cultures demonstrated alloreactivity in 1 treated animal and all untreated animals. In autografts, mean fiber count, nerve density, and percent neural tissue were doubled with FK506 therapy. In allografts, significant neuroregeneration was observed in animals treated with FK506, whereas untreated animals had no regeneration. Treatment with FK506 resulted in a trend toward enhanced axonal regeneration through nerve autografts and allografts in a large-animal model with defined histocompatibility barriers.

Animals↗
PubMed2005

FK506 and anti-CD40 ligand in peripheral nerve allotransplantation.

PURPOSE: Immunomodulatory agents are often combined in organ transplantation to minimize toxicity and enhance therapeutic effect. We hypothesized that combining low-dose FK506 with anti-CD40 Ligand (anti-CD40L mAb) would enhance regeneration through peripheral nerve allografts while preserving immune unresponsiveness. METHODS: Eighty Balb/cJ mice underwent tibial nerve grafting and were randomized to 10 groups treated with combinations of anti-CD40L mAb therapy, low-dose FK506 (0.5 mg/kg/day), high-dose FK506 (2 mg/kg/day), and high-dose cyclosporine (25 mg/kg/day). At 3 weeks, histomorphometry and cytokine secretion assays were performed. RESULTS: Animals receiving low-dose FK506 with anti-CD40L mAb exhibited robust nerve regeneration comparable to the isograft and high-dose FK506 allograft groups. Nerve density was significantly increased in the low-dose FK506 with anti-CD40L mAb group compared to animals receiving anti-CD40L mAb alone (p < 0.05). Combining anti-CD40L mAb with high dose cyclosporine decreased nerve fiber counts, nerve density, and percent nerve (p < 0.05). Interferon-gamma production was markedly elevated in untreated allografts compared to all other treatment groups (p < 0.05). Cytokine secretion was intermediate in the low-dose FK506 alone group and suppressed in all remaining groups. CONCLUSION: When combined with anti-CD40L mAb, low-dose FK506 enhances nerve regeneration without disrupting immune unresponsiveness.

Animals↗
PubMed2004

Use of anti-CD40 ligand monoclonal antibody as antirejection therapy in a murine peripheral nerve allograft model.

Monoclonal antibody directed against CD40 ligand prevents acute allograft rejection in several models of solid-organ transplantation. This study describes the use of CD40 ligand as antirejection therapy in a mouse peripheral nerve allograft model. C3H mice received 8-mm nerve isografts (n = 2) or nerve allografts from C57BL donors. Treated animals (n = 11) received anti-CD40 ligand antibody applied to the graft and by intraperitoneal injections postoperatively. At 3 weeks, nerve histology from treated animals was comparable to isografts, whereas untreated allografts demonstrated virtually no signs of regeneration. Walking-track analysis demonstrated a trend toward improved functional recovery in treated animals. In conclusion, blockade of the CD40 pathway suppresses nerve allograft rejection in mice, and facilitates regeneration comparable to isografts.

Animals↗
PubMed2004

Anti-CD40 ligand monoclonal antibody induces a permissive state, but not tolerance, for murine peripheral nerve allografts.

Anti-CD40 ligand monoclonal antibody prevents the interaction between CD40 and its T-cell-based ligand, thereby resulting in selective inhibition of T cell costimulation without pan-T-cell suppression. This antibody has found application in several animal models of solid organ transplantation. This study investigated use of anti-CD40 ligand antibody to promote acceptance of nerve allografts. In Experiment 1, 40 BALB/cj mice with tibial nerve transplants were administered anti-CD40 ligand antibody, a control antibody, or no treatment. In Experiment 2, 40 BALB/cj mice underwent the same regimen as in Experiment 1, but were later challenged with a second nerve allograft 3 weeks after discontinuation of treatment. Animals treated with anti-CD40 ligand antibody in Experiment 1 exhibited improved functional recovery and greater mean fiber count, fiber density, and percent nerve fiber than animals treated with control antibody or no antibody (P < 0.05). These permissive effects on nerve regeneration were associated with immune unresponsiveness on Elispot assay. The benefit of anti-CD40 ligand therapy did not persist after withdrawal of treatment (Experiment 2). Active blockade of the CD40 costimulatory pathway with murine anti-CD40 ligand antibody therefore induces a permissive state conducive to nerve regeneration across allografts but does not establish long-term tolerance.

Animals↗