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Biomedical subjects

Susan E Mackinnon

Publications and source records attributed to Susan E Mackinnon.

At least 19 recordsLinked to original sources
PubMed2006

Chimerism after vascularized limb versus bone marrow transplantation.

This study used quantitative PCR in the murine model to compare the ability of a limb allograft vs. a comparable dose of marrow suspension to induce chimerism. Female C57Bl/6 mice received a vascularized hindlimb allograft, a comparable dose of 5 x 10 (6) donor bone marrow cells, or a standard dose (20 x 10 (6)) of marrow suspension from male Balb/c donors. All recipients were treated with a regimen based on CD40 costimulation blockade and T cell depletion. Y chromosome-specific quantitative PCR was used to measure chimerism. Most recipients of limb allografts demonstrated low levels of chimerism after 1 week (3/4) and 1 month (3/4). Most recipients of 5 x 10 (6) marrow cells had low levels of chimerism at 1 week (4/6) and only 1/5 after 1 month. All recipients of 20 x 10 (6) cells except one demonstrated either low or high levels of chimerism after 1 week (5/5) and 1 month (5/6). The marrow component of a limb allograft is thus more effective at inducing microchimerism compared to a comparable dose of bone marrow suspension.

Animals↗
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

Choosing the correct functional assay: a comprehensive assessment of functional tests in the rat.

While there are several ways to quantify peripheral nerve regeneration; the true measure of successful outcome is functional recovery. Functional tests are relatively easily conducted in human subjects; however it is more difficult in a laboratory animal. The laboratory rat is an excellent animal model of peripheral nerve injury and has been used extensively in the field of peripheral nerve research. Due to the intense interest in the rat as an experimental model, functional assays have been reported. In an effort to provide a resource to which investigators can refer when considering the most appropriate functional assay for a given experiment, the authors have compiled and tabulated the available functional tests applicable to various models of rat nerve injury.

Animals↗
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 limb allograft survival with CD 40 costimulation blockade, T-cell depletion, and megadose donor bone-marrow transfusion.

The purpose of this study was to determine the efficacy of a treatment regimen consisting of CD 40 costimulation blockade, T-cell depletion, and megadose donor bone marrow transfusion in the limb allograft model. C57Bl/6 mice underwent limb transplantation from Balb/c mice and received MR1 (anti-CD 40 ligand monoclonal antibody), and CD4(+) and CD8(+) T cell-depleting antibodies with and without 120 x 10(6) donor bone-marrow transfusion. Recipients treated only with antibodies showed rejection at 51.4+/-17 (mean+/-SEM) days, while those who also received donor bone marrow had allograft survival of 67+/-16.4 days, with a range up to 91 days. Treated specimens with rejection had less lymphocytic infiltration than untreated controls. Recipients of donor bone marrow also demonstrated early mixed chimerism, which disappeared after 1 month. While allograft survival was prolonged, tolerance was not achieved, and the mechanism of rejection was more consistent with a chronic process.

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

Bridging the neural gap.

A major limitation to overall success in peripheral nerve surgery is time for regeneration. Although one can help speed up the regenerative process to some extent, success is hindered by issues such as number of coaptation sites, supply of donor nerves, and the limitations of nerve substitutes. In the case of a large gap, a nerve graft is often used to fill in the deficit. Autogenous nerve grafts are in limited supply, with sural nerve grafts being the primary source. Alternatives to the standard treatment include vein grafts, synthetic nerve conduits, nerve transfers, and nerve transplantation. Schwann cell-lined nerve conduits and tissue-engineered substitutions are still in their infancy and have some limited clinical application.

Anastomosis, Surgical↗
PubMed2005

Results of reinnervation of the biceps and brachialis muscles with a double fascicular transfer for elbow flexion.

PURPOSE: To report the results of a surgical technique of nerve transfer to reinnervate the brachialis muscle and the biceps muscle to restore elbow flexion after brachial plexus injury. METHODS: Retrospective review was performed on 6 patients who had direct nerve transfer of a single expendable motor fascicle from both the ulnar and median nerves directly to the biceps and brachialis branches of the musculocutaneous nerve. Assessment included degree of recovery of elbow flexion and ulnar and median nerve function including pinch and grip strengths. RESULTS: Clinical evidence of reinnervation was noted at a mean of 5.5 months (SD, 1 mo; range, 3.5-7 mo) after surgery and the mean follow-up period was 20.5 months (SD, 11.2 mo, range, 13-43 mo). Mean recovery of elbow flexion was Medical Research Council grade 4+. Postoperative pinch and grip strengths were unchanged or better in all patients. No motor or sensory deficits related to the ulnar or median nerves were noted and all patients maintained good hand function. No patients required additional procedures to further improve elbow flexion strength. CONCLUSIONS: Transfer of expendable motor fascicles from the ulnar and median nerves successfully can reinnervate the biceps and brachialis muscles for strong elbow flexion. The reinnervation of the brachialis muscle, the primary elbow flexor, as well as the biceps muscle provides an additional biomechanical advantage that accounts for the excellent elbow flexion strength obtained using this technique. Direct coaptation of the nerve fascicles was performed without the need for nerve grafts and there was no functional or sensory donor morbidity.

Adolescent↗
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

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

TH1/TH2 cytokine profile of the immune response in limb component transplantation.

BACKGROUND: The purpose of this study was to define the cytokine secretion pattern during limb allograft rejection and to determine its correlation to differential tissue antigenicity of limb allograft components. METHODS: Twenty-five C57Bl/6 mice (H-2Kb) were randomized to six groups. The experimental groups were recipients of vascularized Balb/c mice (H-2Kd) allografts consisting of skin, muscle, whole limb, or limb with the skin removed or nonvascularized nerve allografts. The unmodified rejection response was studied by histology, flow cytometry, and ELISPOT assay to quantify IFN-gamma (Th1) and IL-4 (Th2) production. RESULTS: The greatest Th1 response was seen in the recipients of allografts composed of skin (973.3 +/- 93 spots/million spleen cells; mean +/- SEM), followed by whole limb (961.3 +/- 86/million), nerve (613.3 +/- 245/million), limb with skin removed (483 +/- 246/million), and then muscle (460 +/- 234/million). Recipients of skin, whole limb, and nerve allografts had the highest IFN-gamma:IL-4 ratios, or greatest Th1 deviation, of 3.1 +/- 0.4, 3.0 +/- 0.2, and 2.9 +/- 0.6, respectively. These were significantly greater than those that received muscle (0.9 +/- 0.3) and limb allografts with skin removed (1.0 +/- 0.4) (p < 0.05). CONCLUSIONS: The skin component produced the greatest Th1 activation of the immune response and appears to be a critical component of the overall antigenicity of the whole limb allograft, as evidenced by the Th2 shift seen when the skin was removed. Muscle produced the least Th1 differentiation, with nerve being intermediate.

Animals↗