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Biomedical subjects

S L Woo

Publications and source records attributed to S L Woo.

At least 91 records · Page 5Linked to original sources
PubMed1997

Evaluation of the effect of joint constraints on the in situ force distribution in the anterior cruciate ligament.

The function of the anterior cruciate ligament was investigated for different conditions of kinematic constraint placed on the intact knee using a six-degree-of-freedom robotic manipulator combined with a universal force-moment sensor. To do this, the in situ forces and force distribution within the porcine anterior cruciate ligament during anterior tibial loading up to 100 N were compared at 30, 60, and 90 degrees of flexion under: (a) unconstrained, five-degree-of-freedom knee motion, and (b) constrained, one-degree-of-freedom motion (i.e., anterior translations only). The robotic/universal force-moment sensor testing system was used to both apply the specified external loading to the intact joint and measure the resulting kinematics. After tests of the intact knee were completed, all soft tissues except the anterior cruciate ligament were removed, and these motions were reproduced such that the in situ force and force distribution could be determined. No significant differences in the magnitude of in situ forces in the anterior cruciate ligament were found between the unconstrained and constrained testing conditions. In contrast, the direction of in situ force changed significantly; the force vector in the unconstrained case was more parallel with the direction of the applied tibial load. In addition, the distribution of in situ force between the anteromedial and posterolateral bundles of the ligament was nearly equal for all flexion angles for the unconstrained case, whereas the anteromedial bundle carried higher forces than the posterolateral bundle at both 60 and 90 degrees of flexion for the constrained case. This demonstrates that the constraint conditions placed on the joint have a significant effect on the apparent role of the anterior cruciate ligament. Specifically, constraining joint motion to one degree of freedom significantly alters both the direction and distribution of the in situ force in the ligament from that observed for unconstrained joint motion (five degrees of freedom). Furthermore, the changes observed in the distribution of force between the anteromedial and posterolateral bundles for different constraint conditions may help elucidate mechanisms of injury by providing new insight into the response of the anterior cruciate ligament to different types of external knee loading.

Animals↗
PubMed1997

In situ forces in the anterior cruciate ligament and its bundles in response to anterior tibial loads.

The anterior cruciate ligament has a complex fiber anatomy and is not considered to be a uniform structure. Current anterior cruciate ligament reconstructions succeed in stabilizing the knee, but they neither fully restore normal knee kinematics nor reproduce normal ligament function. To improve the outcome of the reconstruction, it may be necessary to reproduce the complex function of the intact anterior cruciate ligament in the replacement graft. We examined the in situ forces in nine human anterior cruciate ligaments as well as the force distribution between the anteromedial and posterolateral bundles of the ligament in response to applied anterior tibial loads ranging from 22 to 110 N at knee flexion angles of 0-90 degrees. The analysis was performed using a robotic manipulator in conjunction with a universal force-moment sensor. The in situ forces were determined with no device attached to the ligament, while the knee was permitted to move freely in response to the applied loads. We found that the in situ forces in the anterior cruciate ligament ranged from 12.8 +/- 7.3 N under 22 N of anterior tibial load applied at 90 degrees of knee flexion to 110.6 +/- 14.8 N under 110 N of applied load at 15 degrees of flexion. The magnitude of the in situ force in the posterolateral bundle was larger than that in the anteromedial bundle at knee flexion angles between 0 and 45 degrees, reaching a maximum of 75.2 +/- 18.3 N at 15 degrees of knee flexion under an anterior tibial load of 110 N. The magnitude of the in situ force in the posterolateral bundle was significantly affected by knee flexion angle and anterior tibial load in a fashion remarkably similar to that seen in the anterior cruciate ligament. The magnitude of the in situ force in the anteromedial bundle, in contrast, remained relatively constant, not changing with flexion angle. Significant differences in the direction of the in situ force between the anteromedial bundle and the posterolateral bundle were found only at flexion angles of 0 and 60 degrees and only under applied anterior tibial loads greater than 66 N. We have demonstrated the nonuniformity of the anterior cruciate ligament under unconstrained anterior tibial loads. Our data further suggest that in order for the anterior cruciate ligament replacement graft to reproduce the in situ forces of the normal anterior cruciate ligament, reconstruction techniques should take into account the role of the posterolateral bundle in addition to that of the anteromedial bundle.

Adult↗
PubMed1997

Biomechanics of knee ligament healing, repair and reconstruction.

Injuries of the anterior cruciate ligament (ACL) and the medial collateral ligament (MCL) are common, accounting for 90% of all knee ligament injuries in young and active individuals. During the last decade, our research center has focused on MCL healing and ACL reconstruction. We have found that the MCL heals without intervention after an isolated injury, and that primary repair offers no apparent advantage. After a combined injury of the ACL and MCL, the ACL requires reconstruction, whereas primary repair again contributes little or nothing toward MCL healing. Midsubstance ACL injuries have limited healing ability. Hence, the treatment of choice for a torn ACL in a young, active patient is generally reconstruction with an autograft or allograft. However, the appropriate replacement graft and reconstruction technique to use are still debated. Current research efforts have been placed on investigating the magnitude and direction of in situ forces in the human ACL. We use a six-component universal force moment sensor combined with a six-degree-of-freedom (DOF) robotic manipulator to learn as well as to reproduce the six-DOF motion of the knee before and after ACL injury. This way, the in situ force in the ACL under an anterior posterior tibial load of 110 N was obtained. This methodology should make it possible to obtain the needed data to aid in better understanding of ACL reconstruction and possible development of improved clinical management.

Animals↗
PubMed1997

The effects of age on rabbit MCL fibroblast matrix synthesis in response to TGF-beta 1 or EGF.

In this study, we examined the effects of age on collagen and total protein synthesis by ligament fibroblasts in response to growth factors. Three different doses of transforming growth factor-beta 1 (TGF-beta 1) or epidermal growth factor (EGF) were individually added to in vitro fibroblast cultures from the medial collateral ligament (MCL) of skeletally immature (age 3 months), mature (age 12 months) and senescent (age 48-51 months) rabbits. Analysis of the effects of age revealed that fibroblasts from senescent rabbits produced significantly less collagen in response to TGF-beta 1 or EGF stimulation when compared to fibroblasts from immature rabbits. Furthermore, increased age was found to result in significant reductions in the baseline levels of collagen synthesis but not total protein synthesis. Additionally, collagen and total protein synthesis by MCL fibroblasts were significantly affected by the TFG-beta 1 dose, but not by the EGF dose. When fibroblasts were normalized to their own controls, the increase in collagen and total protein synthesis due to TGF-beta 1 and EGF for the senescent group were found to be greater than those for the skeletally immature rabbits at all doses. This demonstrates that MCL fibroblasts from senescent rabbits are responsive to growth factors.

Aging↗
PubMed1997

Adenovirus-mediated suicide gene therapy for experimental bladder cancer.

OBJECTIVES: To determine the feasibility, safety, and efficacy of suicide gene therapy using adenoviral-mediated herpes simplex virus thymidine kinase gene (HSV-tk) and the prodrug ganciclovir (GCV) in a murine model of human transitional cell carcinoma. METHODS: We used a replication-defective adenoviral construct containing the beta-galactosidase gene (ADV/Rous sarcoma virus [RSV]-beta-gal) as a control or ADV/RSV-tk as the therapeutic vector under the transcriptional control of the RSV long-terminal repeat promoter. Transduction efficiency was assessed in vitro by infection of MBT-2 cells with ADV/RSV-beta-gal at various multiplicities of infection (MOI) utilizing 5-bromo-4-chlor-3-indolyl-beta-D-galactoside (X-gal) staining. Sensitivity of MBT-2 cells to the therapeutic vector was determined after infection with ADV/RSV-tk with or without GCV. Subcutaneous tumors were established in syngeneic C3H/He female mice with 5 x 10(5) MBT-2 cells. Optimal dosing of ADV/RSV-tk was determined by direct percutaneous tumor injection with increasing viral doses and treatment with GCV. Treatment efficacy, long-term survival, and toxicity were determined in separate, similar, controlled experiments. RESULTS: In vitro studies indicated greater than 95% transduction 96 hours after inoculation at an MOI of 3000 and a greater than 95% cell death rate with RSV-tk + GCV at an MOI of 61 or greater. In vivo experiments demonstrated an optimal viral dose of 3 x 10(8) plaque-forming units (pfu) and a greater than fourfold reduction in tumor growth for the animals treated with ADV/RSV-tk compared with control animals (P = 0.0013). Toxicity was limited to histologic evidence of hepatitis with ADV/RSV-tk doses greater than 3 x 10(8) pfu + GCV. Long-term survival of treatment animals was significantly increased over that of control animals (59%, P = 0.0001). CONCLUSIONS: ADV/RSV-tk with GCV treatment results in efficient gene transfer in vitro and provides effective therapy in experimental murine bladder cancer by significantly inhibiting tumor growth and improving host survival.

Adenoviridae↗
PubMed1997

Tensile properties of canine intrasynovial and extrasynovial flexor tendon autografts.

This study compared the biomechanical properties of intrasynovial and extrasynovial flexor tendon autografts in an adult canine model. Flexor digitorum profundus (FDP) tissue from the fifth toe of the hindpaw was harvested and transplanted as an intrasynovial graft to the second toe of the left forepaw of each animal. Peroneus longus tendon from the lateral compartment of the hind leg served as the source for the extrasynovial graft that was transplanted to the fifth toe of each dog's left forepaw. The second and fifth FDP tendons of the right forepaw constituted the respective contralateral controls. Postoperatively, each animal underwent a regimen of daily controlled passive mobilization. Three and 6 weeks after grafting, 6 animals were euthanized and their grafts evaluated for gliding function and tensile properties. Results reveal significantly greater angular rotation of the proximal interphalangeal joint in the digits that received intrasynovial grafts relative to those that received transplanted extrasynovial tendon at both 3 and 6 weeks postoperatively. The linear stiffness of the tendons receiving extrasynovial graft significantly exceeded that of the intrasynovial group. These findings correlated with histologic data that postoperative adhesions existed in the specimens with an extrasynovial graft. In addition, the extrasynovial tendon graft complex exhibited significantly higher ultimate loads than intrasynovial tendon graft complex at 6 weeks.

Animals↗
PubMed1997

The effect of anterior cruciate ligament graft fixation site at the tibia on knee stability: evaluation using a robotic testing system.

Despite its current popularity and relative success, endoscopic reconstruction of the anterior cruciate ligament (ACL) using a bone-patellar tendon-bone (BPTB) graft has not yet been perfected. Using a recently developed robotic/UFS testing system, we assessed the overall stability of porcine knees following ACL reconstruction with different sites of tibial graft fixation--proximal, central, and distal. Testing of the intact knee was performed first to determine the normal anterior-posterior (A-P) displacements and in situ forces of the ACL under 110 N of anterior tibial loading of 30 degrees, 60 degrees, and 90 degrees of knee flexion. The knee was then reconstructed with a BPTB autograft, and the distal end of the graft was fixed sequentially at three different locations in each specimen--proximal, central, distal. A-P testing was repeated for each fixation site, and the resulting knee kinematics and the in situ forces of the grafts were compared to the intact case. The site of tibial fixation was demonstrated to have a significant effect on the resulting anterior displacement and internal rotation of the tibia as well as the in situ forces of the graft. Proximal fixation produced the most stable knee (A-P displacements reduced to 120% of intact at 30 degrees and 170% at 90 degrees), becoming significantly less stable with more distal fixation. These results suggest that proximal graft fixation may provide the most acute stability of the reconstructed knee.

Animals↗
PubMed1997

Suture methods for flexor tendon repair. A biomechanical analysis during the first six weeks following repair.

This review describes the evolution of recently developed multi-strand, multi-grasp flexor tendon suture techniques. Analyses of digital angular joint rotation, tendon excursion, and ultimate tensile load at the time of repair and at three and six weeks following repair allowed comparison of a variety of innovative grasping and non-grasping multi-strand techniques. The first series of experiments describes an analysis of the Tajima, Tsuge, Savage, Kessler, double loop locking suture, and recently developed eight-strand suture techniques at the time of repair. The Tajima, Savage, and eight-strand repair methods were found to have statistically significant improved gliding function compared to those methods that featured external knots (Kessler and Tsuge) and methods that tended to bunch at the repair site (double loop locking suture). With regard to ultimate tensile load, the eight-strand repair was found to have the greatest strength (69N) of all tested methods (p < 0.05). The second series of experiments examined the Tajima, Kessler, Savage, and eight-strand suture methods at three and six weeks following tendon repair. A high percentage of failure within the Kessler repairs precluded their inclusion for final comparative analysis. The results for the remaining three techniques were normalized (experimental/control) to allow inter-group comparison. For intrasynovial tendon repair gliding function, all prepared specimens were found to have significantly less tendon excursion, proximal interphalangeal joint rotation, and distal interphalangeal joint rotation than their respective controls. However, no statistical differences were noted in gliding function between the Tajima, Savage, and eight-strand repair at three and six weeks (p < 0.05). Ultimate tensile testing ascertained that the eight strand method demonstrated significantly greater strength at three (52.6N) and six (70.9N) weeks than both the Tajima and Savage techniques (p < 0.05), while the Savage repair had significantly greater strength than the Tajima repair (p < 0.05). On the basis of these findings, we suggest that early controlled active motion protocols be devised using the multi-strand multi-grasp techniques, as exemplified by the eight strand tendon repair method, in an effort to achieve consistently improved results for intrasynovial flexor tendon repairs.

Animals↗
PubMed1997

Neurotoxicity of intracerebral injection of a replication-defective adenoviral vector in a semipermissive species (cotton rat).

The neurotoxicity of an adenoviral vector (Adv.RSVtk) carrying the gene for herpes simplex virus thymidine kinase (HSVtk) was tested in the cotton rat, a semipermissive host. Adv.RSVtk was injected intracerebrally in cotton rats at a dose of 5.0 x 10(6) or 7.5 x 10(7) p.f.u. No signs of illness were observed. Histological inspection at 12 and 28 days after injection showed inflammation of the ependyma and choroid plexus and at the injection site. No demyelination, viral inclusions, cerebral edema, necrosis, cavities or vascular necrosis were seen in the brains. There was no significant difference between animals injected with 5.0 x 10(6) or 7.5 x 10(7) p.f.u., nor was there a difference between animals analyzed at 12 or 28 days after vector injection. This inflammation was similar in animals that had been preimmunized with wild-type virus and in animals that had been treated with ganciclovir. No histopathology, was observed in the lungs of the animals and no replication-competent virus was detected. These experiments indicate that Adv.RSVtk has limited neurotoxicity which would not prohibit its use in a limited phase I clinical trial in humans that have malignant tumors of the central nervous system.

Animals↗
PubMed1997

Introduction to PCR/OLA/SCS, a multiplex DNA test, and its application to cystic fibrosis.

The field of medical, molecular diagnostics has grown rapidly over the last few years, becoming increasingly informative to both clinician and patient. As genes associated with specific diseases have been discovered and sequenced, many genotype-phenotype relationships have been defined. For those genetic diseases with associated, defined, gene mutations, sophisticated DNA diagnostic tests are being developed. As an example, the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, is associated with Cystic Fibrosis (CF). We have developed a new molecular diagnostic technology, PCR/OLA/SCS, and applied it first to the diagnosis of CF. Test design in the field of molecular diagnostics must consider such characteristics as specificity, sensitivity, ease and speed of protocol, multiplex capacity, and cost. PCR/OLA/SCS addresses these requirements. Polymerase Chain Reaction (PCR) is widely used in both diagnostics and research. We have combined well established PCR technology with Oligonucleotide Ligation Assay (OLA) and Sequence-Coded Separation (SCS), two relatively new technologies.

Alleles↗
PubMed1997

Adenoviral-mediated herpes simplex virus thymidine kinase gene transfer: regression of hepatic metastasis of pancreatic tumors.

Pancreatic cancer is the fifth leading cause of cancer death in the United States. Most patients have obvious metastases or locally advanced disease at the time of presentation. Surgical resection does not significantly change the clinical outcome. Combination chemotherapy induces a partial response but overall survival remains low. The aim of this study was to evaluate the feasibility of adenovirus-mediated suicide gene transduction as a therapeutic approach for pancreatic cancer. A cell line was established from a murine pancreatic ductal adenocarcinoma and intrahepatic tumors were generated by inoculation of pancreatic cancer cells into the left lateral liver lobe. Transduction efficiency was characterized in vitro and in vivo. Intrahepatic tumors were treated by intratumoral adenovirus injection in combination with intraperitoneal administration of ganciclovir. Adenovirus-mediated herpes simplex virus (HSV)-thymidine kinase (tk) gene expression followed by ganciclovir treatment was highly efficient in inhibiting pancreatic cancer cell proliferation in vitro. The proliferation of nontransduced cells was significantly reduced in the presence of HSV-tk expressing cells. Intrahepatic inoculation of pancreatic cancer cells leads to successful formation of solid adenocarcinomas in syngeneic recipients. Ad.RSV-tk injection of the tumor followed by intraperitoneal ganciclovir application caused highly significant tumor volume reduction and necrosis. These results indicate that transduction of the HSV-tk gene followed by ganciclovir is highly efficient for growth inhibition of hepatic metastases of pancreatic carcinoma.

Adenocarcinoma↗
PubMed1997

The role of interleukin-2 in combination adenovirus gene therapy for head and neck cancer.

Interleukin-2 (IL-2) gene therapy alone and in combination with the herpes thymidine kinase gene (tk) was used to evaluate immunological responses and antitumor effects in head and neck cancer. Established floor of mouth squamous cell carcinomas in C3H/HeJ mice were directly injected with recombinant adenoviral vectors carrying both therapeutic and control genes. One week after adenoviral gene transfer, only the animals treated with combination IL-2+tk or tk alone demonstrated significant tumor regression. Residual tumors were harvested for microscopic evaluation and immunohistochemistry staining, which revealed a predominance of CD8+ lymphocytes in the tumor beds of the animals treated with IL-2. To evaluate the systemic immune effects of IL-2, animals treated with single or combination gene therapy received a second site challenge with parental tumor cells or a heterologous but syngeneic sarcoma cell line. Mice treated with combination IL-2 and tk demonstrated a protective systemic immunity specific to the parental tumor cell line, whereas no systemic immune response was evident in mice receiving IL-2 alone. In a separate experiment, a range of concentrations of the adenovirus IL-2 vector were used to treat established tumors. Even with the maximal single-dose adenovirus concentration, IL-2 alone was ineffective as a single therapy. These results support the use of adenovirus-mediated gene transfer of IL-2 as an effective immunotherapy when used adjuvantly with the tk "suicide gene".

Adenoviridae↗
PubMed1997

Hepatic insulin gene expression as treatment for type 1 diabetes mellitus in rats.

Type 1 diabetes mellitus is caused by a lack of insulin that results from the autoimmune destruction of the pancreatic beta-cells. Severe diabetes, if not controlled by periodic insulin injections, can lead to ketoacidosis and death. We have previously shown that sustained low level production of insulin in the liver of diabetic rats prevented their death from complications of diabetes. To test the hypothesis that there is a window of serum insulin concentrations that can prevent ketoacidosis without significant risk of hypoglycemia secondary to hyperinsulinemia, rats were infused with various doses of a recombinant retrovirus encoding an engineered rat preproinsulin-1 gene. The gene was engineered to allow processing into mature insulin by the protease furin. At the lower doses tested, fatal ketoacidosis was prevented, but the rats exhibited nonfasting hyperglycemia. At intermediate doses, which resulted in serum insulin concentrations of 1.6 mg/ml, the rats achieved near-normoglycemia and no serum ketones. These rats did not exhibit hypoglycemia even during a 24-h fast. At high virus doses, the animals achieved nonfasting normoglycemia but exhibited hypoglycemia during the fast. In conclusion, we have defined a therapeutic window of hepatic insulin expression that provides protection against ketoacidosis without significant risk of hypoglycemia. This window of sustained hepatic insulin expression might permit its development into a novel treatment modality for the prevention of ketoacidosis in patients with severe insulin-dependent diabetes mellitus.

Animals↗
PubMed1997

Effect of growth factors on the proliferation of ligament fibroblasts from skeletally mature rabbits.

Growth factors have been shown to stimulate fibroblast proliferation during wound and ligament healing. In this study, we analyzed individual effects of eight growth factors in vitro on the proliferation of fibroblasts from the medial collateral (MCL) and anterior cruciate (ACL) ligaments of skeletally mature rabbits. We compared the proliferative response of growth factor-treated and nontreated fibroblasts of both ligaments. The growth-factor treated fibroblasts of the MCL and ACL were also compared. We found that the fibroblasts exposed to epidermal growth factor, basic fibroblast growth factor and platelet-derived growth factor-BB proliferated significantly more than untreated fibroblasts. Acidic fibroblast growth factor at a dose of 1.0 ng/ml caused significant increases in fibroblast proliferation only in the MCL. Transforming growth factor-beta 1, insulin-like growth factor-1, platelet-derived growth factor-AA, and interleukin-1 alpha did not significantly stimulate fibroblast proliferation. MCL fibroblasts generally did not proliferate significantly more than ACL fibroblasts with the exception of MCL fibroblasts exposed to the highest doses of basic fibroblast growth factor, acidic fibroblast growth factor and platelet-derived growth factor-BB. The data were also compared with those obtained earlier using fibroblasts from skeletally immature rabbits (Schmidt et al., JOR 1995). The proliferative response of both the MCL and the ACL fibroblasts was found to decrease with skeletal maturation. Thus, our findings suggest that animal age and fibroblast origin are important factors in determining the proliferative response to growth factors.

Animals↗
PubMed1997

Medial collateral knee ligament healing. Combined medial collateral and anterior cruciate ligament injuries studied in rabbits.

We examined the histological appearance and biochemical properties of the healing medial collateral ligament (MCL) of a rabbit knee after combined MCL and anterior cruciate ligament (ACL) injury treated with ACL reconstruction and with or without MCL repair. By so doing, we hoped to understand better our previous bomechanical observations (Ohno et al. 1995) and possibly learn where to focus future investigation into improving the quality of the healing MCL. Ligaments were examined at 6 and 12 weeks of healing. We found healing of all ligaments with hypercellularity and fibroblast elongation along the axis of loading, as expected. Unexpected, however, was the finding of multiple osteophytes in both the repaired and nonrepaired specimens at the medial borders of the joint and at the MCL insertions. These were felt to affect possibly the biomechanics of the MCL by causing stress risers at the point where they undermine the ligament. Biochemically, we demonstrated a correlation between collagen content and hydroxypyridinium crosslinks and modulus of elasticity. While this implies that the modulus is dependent on collagen content and hydroxypyridinium crosslink density, modulus is also probably dependent on other factors such as collagen organization, type and internal structure. Overall, the detailed characterization and correlation between the histological, biochemical, and biomechanical properties of the healing MCL in the severe knee injury model provide insight into the functional behavior of the healing MCL.

Animals↗
PubMed1997

Viral vector-mediated gene therapy for hemophilia B.

Over the past five years, significant advances have been made in the development of novel viral vector systems for the treatment of hemophilia B by somatic gene therapy. At present, both a sustained but partial or a complete but transient correction of the hemophilia B phenotype have been observed in a clinically relevant animal model. Present efforts are being directed toward the development of safe, effective and persistent methods of virally-mediated gene transfer to achieve the complete restoration of normal hemostasis in individuals with hemophilia B.

Adenoviridae↗
PubMed1997

The Marshall R. Urist Young Investigator Award. Autogenous flexor tendon grafts. Biologic mechanisms for incorporation.

To examine the hypothesis that different types of dense regular connective tissue may have different repair mechanisms within the synovial space, intrasynovial and extrasynovial autogenous donor flexor tendon grafts were placed within the synovial sheaths of the medial and lateral forepaw digits of dogs. Histologic, ultrastructural, biochemical, and biomechanical analyses were done between 10 days and 6 weeks after tendon grafting. Intrasynovial tendon grafts remained viable when transferred to the synovial space and appeared to heal through an intrinsic process with preservation of the gliding surface and improved functional characteristics. Extrasynovial tendon grafts functioned as a scaffolding for the early ingrowth of new vessels and cells. Early cellular necrosis consistently was followed by the ingrowth of fibrovascular adhesions from the periphery. The formation of dense peripheral adhesions, obliterating the gliding surface of the tendon, led to diminished tendon excursion and proximal interphalangeal joint rotation.

Animals↗