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Biomedical subjects

J R Lieberman

Publications and source records attributed to J R Lieberman.

At least 19 recordsLinked to original sources
PubMed2005

Effects of the proteasome inhibitor bortezomib on osteolytic human prostate cancer cell metastases.

Prostate adenocarcinoma is the most common malignancy diagnosed in males, and bone metastases remain a significant source of morbidity and mortality in this population. The ubiquitin-proteasome cascade is responsible for the degradation of intracellular proteins, and this pathway is thought to play an essential role in the development of malignancies by altering the levels of various proteins involved in the regulation of cell division. Proteasome inhibitors represent a class of chemotherapeutic agents that have been shown to inhibit tumor growth by a number of different mechanisms. Using a murine intratibial injection model, we examined the effects of the proteasome inhibitor bortezomib on the establishment and progression of osteolytic bone lesions induced by human CaP cells (PC-3 cell line). In this study, the intravenous administration of bortezomib (1 mg/kg) did not prevent the initial formation of osteolytic lesions but did appear to inhibit their growth in a time-dependent fashion. In contrast, bortezomib therapy effectively inhibited the establishment and progression of subcutaneous PC-3 tumors, which served as a positive control. These results suggest that proteasome inhibitors such as bortezomib may represent a novel adjunctive therapy for the treatment of osteolytic skeletal metastases, especially when treatment is initiated early during the disease process.

Animals↗
PubMed2005

Healing of a critical-sized defect in the rat femur with use of a vascularized periosteal flap, a biodegradable matrix, and bone morphogenetic protein.

BACKGROUND: The purpose of this study was to evaluate the osseous healing of a critical-sized femoral defect in a rat model with use of recombinant human bone morphogenetic protein-2 (rhBMP-2), a matrix fabricated of D,D-L,L-polylactic and hyaluronan acid (OPLA-HY), and a vascularized periosteal flap. METHODS: The carrier matrix OPLA-HY with or without rhBMP-2 was implanted in a 1-cm-long femoral defect and secured with a plate and screws. In some groups, a vascularized periosteal flap was harvested from the medial surface of the tibia. In group 1, the femoral defects in the animals were filled with the OPLA-HY matrix alone; in group 2, the OPLA-HY matrix was covered by the vascularized periosteal flap; in group 3, 20 mug of rhBMP-2 was added to the OPLA-HY matrix; and in group 4, the femoral defect containing the OPLA-HY matrix and 20 mug of rhBMP-2 was wrapped circumferentially by the vascularized periosteal flap. The presence and density of new bone formation in the femoral defect were evaluated radiographically, histologically, and with histomorphometry at four and eight weeks postoperatively. RESULTS: Groups 1 and 2, which were not treated with rhBMP-2, showed no radiographic or histologic evidence of mature bone formation at four or eight weeks. Both groups 3 and 4, which were treated with rhBMP-2, demonstrated excellent bone formation. However, with the periosteal flap, group 4 demonstrated more bone formation on histomorphometric analysis at eight weeks (43.1%) than did group 3 (28.3%) (p < 0.01). Additionally, heterotopic bone formed outside the boundaries of the defect in eight of the fifteen animals in group 3, which had no periosteal flap. CONCLUSIONS: Bone-tissue engineering with use of the OPLA-HY matrix and rhBMP-2 produced good bone formation in the rat femoral defect model. However, the addition of a vascularized periosteal flap significantly increased bone formation within the boundaries of the defect and prevented heterotopic ossification.

Animals↗
PubMed2004

Regional gene therapy to enhance bone repair.

Gene therapy presents a novel approach to the treatment of challenging bone loss problems. Recombinant, osteogenic growth factors are now available to enhance bone repair, particularly in those applications related to the treatment of fracture nonunions and the enhancement of fusion of the spine. However, there is concern that a single dose of an exogenous protein will not induce an adequate osteogenic signal in many patients, particularly in those cases where there is compromise of host bone and the surrounding soft tissue. Transfer of genes encoding osteogenic proteins has the potential to overcome the delivery problems associated with the use of the proteins themselves. Bone healing is an attractive application for gene therapy, because long-term protein production is not necessary for many bone repair problems. Therefore, the development of gene therapy strategies to treat bone repair problems promises to be easier than the application of gene therapy to treat chronic diseases. The purpose of this review is to highlight the advantages, disadvantages and clinical potential of various gene therapy strategies to enhance bone repair.

Animals↗
PubMed2003

Differences in the cytokine profiles associated with prostate cancer cell induced osteoblastic and osteolytic lesions in bone.

Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It is hypothesized that osteoclastogenesis is a critical component in the development of skeletal metastases. These findings, however, were generally noted in predominantly osteolytic lesions. The pathophysiology of osteoblastic lesions remains unknown but the type of bone lesion formed may be influenced by the cytokines produced by prostate tumors. To test this theory, we implanted PC-3 and LAPC-9 cells into the tibias of SCID mice. These mice were sacrificed at 1, 2, 4, 6, and 8 weeks after implantation and histologic analysis was performed on these tibias. PCR analysis was also performed on bulk tumors. The results showed that the PC-3 implanted tibias developed pure osteolytic lesions while the LAPC-9 implanted tibias developed pure osteoblastic lesions on radiographs. Analysis of tibias after injection with PC-3 cells revealed progressive osteolytic lesions with abundant osteoclast activity at 2 weeks and destruction of the proximal tibia at 6 weeks after cell implantation. In contrast, the LAPC-9 cells formed osteoblastic lesions six weeks after cell injection. There were rare osteoclasts prior to the establishment of the osteoblastic lesions but greater osteoclast activity was noted with remodeling of the osteoblastic lesion 8 weeks after implantation of the tumor cells. PCR analysis revealed that PC-3 cells produced RANKL, IL-1, and TNF-alpha, which are associated with osteoclastogenesis. In contrast, LAPC-9 cells produced osteoprotegerin, which blocks osteoclast production and no detectable levels of RANKL or IL-1 and only minimal amounts of TNF-alpha were noted. These cells secreted BMP-2, -4, -6, and IL-6, which are associated with bone formation. These results suggest that the role of the osteoclast in the development of a metastatic lesion is variable depending on the phenotype of the prostate cancer cells, and that tumor-induced osteolysis may not be required for osteoblastic metastases.

Animals↗
PubMed2003

Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.

BACKGROUND: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. METHODS: This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. RESULTS: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen. CONCLUSIONS: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Administration, Oral↗
PubMed2003

Tissue-engineered cartilage and bone using stem cells from human infrapatellar fat pads.

Multipotential processed lipoaspirate (PLA) cells extracted from five human infrapatellar fat pads and embedded into fibrin glue nodules, were induced into the chondrogenic phenotype using chondrogenic media. The remaining cells were placed in osteogenic media and were transfected with an adenovirus carrying the cDNA for bone morphogenetic protein-2 (BMP-2). We evaluated the tissue-engineered cartilage and bone using in vitro techniques and by placing cells into the hind legs of five severe combined immunodeficient mice. After six weeks, radiological and histological analysis indicated that the PLA cells induced into the chondrogenic phenotype had the histological appearance of hyaline cartilage. Cells transfected with the BMP-2 gene media produced abundant bone, which was beginning to establish a marrow cavity. Tissue-engineered cartilage and bone from infrapatellar fat pads may prove to be useful for the treatment of osteochondral defects.

Adipose Tissue↗
PubMed2002

Prefabrication of bone by use of a vascularized periosteal flap and bone morphogenetic protein.

The purpose of this pilot study was to prefabricate a vascularized bone graft by using a vascularized periosteal flap containing osteoprogenitor cells, a structural matrix, and recombinant human bone morphogenetic protein-2 (rhBMP-2). In a rat model, a periosteal flap vascularized by the saphenous artery and vein was dissected off the medial surface of the tibia. This flap consisted of three layers-periosteum, muscle, and fascia-and was tubed on itself to form a watertight chamber that was then transferred on its vascular pedicle to the groin. A total of 78 vascularized periosteal chambers were constructed in 39 animals and divided into 10 groups. In group 1, the periosteal chamber was left empty. Groups 2, 3, and 4 consisted of the periosteal flap and rhBMP-2, but in group 3, the proximal vascular pedicle was ligated, and in group 4, the flap was harvested without the periosteal layer and turned inside out. Groups 5 through 10 consisted of the vascularized periosteal flap containing several different structural matrices (calcium alginate spheres, polylactic acid, or demineralized bone matrix) with or without rhBMP-2. Animals were killed at 2, 4, or 8 weeks in each group. The presence and density of any new bone formation was evaluated both radiologically and histologically. Significant bone formation was seen only in those periosteal flaps containing rhBMP-2 and either the calcium alginate or polylactic acid matrix. New bone formation increased both radiologically and histologically from 2 weeks to 8 weeks only in the periosteal flaps containing the polylactic acid matrix and rhBMP-2. This preliminary study therefore suggests that four factors-blood supply, osteoprogenitor cells in the periosteal layer, a biodegradable matrix, and rhBMP-2-are required for optimal prefabrication of a vascularized bone graft.

Alginates↗
PubMed2001

Poly(lactide-co-glycolide)/hydroxyapatite delivery of BMP-2-producing cells: a regional gene therapy approach to bone regeneration.

Currently, functional treatment of fracture non-unions and bone loss remains a significant challenge in the field of orthopaedic surgery. Tissue engineering of bone has emerged as a new treatment alternative in bone repair and regeneration. Our approach is to combine a polymeric matrix with a cellular vehicle for delivery of bone morphogenetic protein-2 (BMP-2), constructed through retroviral gene transfer. The objective of this study is to develop an osteoinductive, tissue-engineered bone replacement system by culturing BMP-2-producing cells on an osteoconductive, biodegradable, polymeric-ceramic matrix. The hypothesis is that retroviral gene transfer can be used effectively in combination with a biodegradable matrix to promote bone formation. First, we examined the in vitro attachment and growth of transfected BMP-producing cells on a PLAGA-HA scaffold. Second, the bioactivity of the produced BMP in vitro was evaluated using a mouse model. It was found that the polymer-ceramic scaffold supported BMP-2 production, allowing the attachment and growth of retroviral transfected, BMP-2-producing cells. In vivo, the scaffold successfully functioned as a delivery vehicle for bioactive BMP-2, as it induced heterotopic bone formation in a SCID mouse model.

Animals↗
PubMed2001

Hip function in patients >55 years old: population reference values.

The purpose of this study was to establish population values for hip function for patients of different ages using the validated WOMAC scoring system and the traditional Harris hip scoring system. A random sample of 184 individuals who had no prior history of hip or knee pain or pathology was evaluated. The average WOMAC scores for pain, function, and stiffness were 0.01, 1.8, and 0.4. The average Harris hip score was 94 +/- 8.2. No significant correlation was noted between the summary WOMAC score, the WOMAC stiffness or pain subscales, or the overall Harris hip score for any of the 3 age groups studied. Patients with complaints in other joints, such as the back and neck, had lower WOMAC and Harris hip scores. Adults who are healthy and do not have a prior history of hip or knee pathology do not show a significant decline in hip function as they grow older. A deterioration in the function of a total hip arthroplasty over time cannot be attributed solely to the aging process.

Aged↗
PubMed2000

The accuracy of assessing total hip arthroplasty outcomes: a prospective correlation study of walking ability and 2 validated measurement devices.

The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the SF-36 are used to assess subjective outcome after total hip arthroplasty (THA). Although these indices have been validated, neither the WOMAC nor the SF-36 has been tested for accuracy against objective data in this clinical setting. Thirty osteoarthritic patients undergoing elective primary THA were subjectively evaluated preoperatively and 1 year postoperatively with the WOMAC and the SF-36 and objectively evaluated at the same interval with basic stride analysis and the 6-minute walk test. Correlation analysis of the subjective and objective data (both perioperative improvement and postoperative absolute scores) yielded Pearson coefficients of r = 0.50-0.81. This work demonstrates a sound statistical relationship between walking ability and the functional aspects of the WOMAC and the SF-36, supporting the use of these instruments in assessing the functional outcome after THA.

Aged↗
PubMed2000

Symptomatic osteonecrosis of the hip after orthotopic liver transplantation.

Patients who require long-term steroid use for immunosuppression after organ transplantation are at risk for the development of osteonecrosis. The purpose of this study was to determine the prevalence of symptomatic osteonecrosis of the hip in patients who were managed with corticosteroids for immunosuppression after orthotopic liver transplantation. We reviewed the relationship of the administration and dosage of steroids in 203 patients who underwent orthotopic liver transplantation. Overall, 29 of the 203 patients (14%) complained of hip pain, but only 3 patients (2%) developed symptomatic osteonecrosis of the hip. The osteonecrosis was diagnosed an average of 31 months after transplantation (range, 26-38 months). There was no association noted between steroid dose and the development of osteonecrosis. Routine screening for osteonecrosis of asymptomatic liver transplant patients is not necessary.

Adrenal Cortex Hormones↗
PubMed2000

The orthopaedic surgeon and industry. Ethics and industry incentives.

Physicians may receive various gifts and incentives from companies that make pharmaceuticals and medical devices. Although such incentives may benefit patients and physicians, they often pose serious conflicts of interest that violate a physician's professional responsibility. The physician-patient relationship is predicated on the physician acting in the best interest of the patient. The application of medical knowledge to complex clinical circumstances is difficult, even without biased sources of information and internal conflicts attributable to financial incentives. Yet, industry resources often are dedicated to the dissemination of information and incentives aimed to influence decisions not necessarily aimed at the goals of the patient. Physicians often are unaware of the nature of the incentives and commonly deny their demonstrated impact. Any incentive that is designed to impede, rather than enhance, the clinician's ability to make optimal patient care decisions is unethical for a physician to accept. These incentives should play no role in the practice of orthopaedic surgery.

Ethics, Medical↗
PubMed2000

Achieving informed consent when patients appear to lack capacity and surrogates.

Obtaining informed consent is a frequent and important part of the practice of orthopaedic surgery. However, the process can be complicated, especially when there are impediments to communication and unusual decisions. An approach that considers each of the elements of informed consent permits the clinician to enhance the role of autonomy in patient decisions while maximizing the probability of achieving successful informed consent. Attending to (and testing when necessary) a patient's capacity to make decisions, ensuring comprehension of the clinical circumstances and proposed intervention and it's risks and benefits, and evaluating the decision-making mechanism are essential steps. A patient's capacity to participate in informed consent at times may be enhanced by selected interventions and may require serial reevaluation to identify the optimal time to discuss the issues. Implied consent has an important but delimited role in emergent circumstances. Prospective elicitation of patient preferences and delineation of surrogate decision makers can substantially enhance the ease and efficiency of informed consent while matching care with patient goals.

Aged↗
PubMed2000

Osteoinductive applications of regional gene therapy: ex vivo gene transfer.

Gene therapy represents the new frontier of medical science. Currently, there are no completely satisfactory treatment options for bone repair problems such as fracture nonunion, revision total joint arthroplasty, tumor resections, and fusions of the spine. Autogenous bone grafts, allograft implants, and prosthetic implants have been used to treat these problems. However, there are significant limitations associated with these methods including limited supply and limited osteogenic potential. Gene therapy, involving the manipulation of endogenous cells to generate specific proteins, offers a potential solution for these problems. By transferring genes into cells at a specific anatomic site, the osteoinductive properties of growth factors can be used at physiologic doses for a sustained period to facilitate a more significant healing response. Successful gene therapy involves four key steps: transduction, transcription, translation, and expression. To achieve gene transduction of a target cell, gene therapy models use vectors to enhance the entry and expression of exogenous deoxyribonucleic acid into the target cell's nucleus. The transduction of a gene can be performed via either an ex vivo or an in vivo approach. Although there are many potential target cells for gene therapy, the specific anatomic site, the quality of the bone, and the soft-tissue envelope, will influence the selection of the target cells for regional gene therapy. Gene therapy vectors delivered to a treatment site in osteoconductive carriers have yielded promising results. Several investigators have shown exciting results using ex vivo and in vivo regional gene therapy in animal models. Comparative studies and human clinical trials have not yet been performed but are necessary to identify the optimal genes and dosages for each specific application of regional gene therapy. In the future, the treatment options for bone loss problems will represent a clinical continuum based on the anatomic site, the condition of the target tissue bed, and the desired duration of protein production.

Animals↗
PubMed2000

The Frank Stinchfield Award. Influence of cement technique on the interface strength of femoral components.

The optimal surface finish for polymethylmethacrylate cemented femoral components remains controversial. Concerns about early debonding of the prosthesis-cement interface have led surgeons to use roughened surfaces to enhance the cement-prosthesis bond. However, loosening of roughened stems is associated with the generation of excessive wear debris. The purpose of the current study was to determine whether the time to cementation influenced the cement-prosthesis bond of four roughened cobalt chrome surfaces (60 grit-blasted, 10 grit-blasted, 10 grit-blasted with polymethylmethacrylate precoating, glass bead-blasted) and one polished cobalt chrome surface. Fixation strength was assessed using mechanical pushout and tensile testing. Roughened and polymethylmethacrylate precoated surfaces had significantly greater tensile and shear strengths at early cementation times compared with polished surfaces. However, roughened components had significant decreases in tensile and shear strengths as cementation time increased from 2 to 4 minutes and 2 to 6 minutes. In contrast, tensile and shear strengths for the polished surface were significantly lower than for the roughened surfaces and did not change with longer cementation times. When using a roughened or precoated cemented femoral component, the surgeon should consider cementing earlier with wetter cement to maximize the cement-prosthesis bond. When implanting a polished femoral component, it is preferable that the cement is doughy, because the cement-prosthesis bond is not influenced by the wetness of the cement and it is easier to maintain the orientation of the femoral component.

Arthroplasty, Replacement, Hip↗
PubMed1999

Gene therapy for osteoinduction.

One application of gene therapy that holds great promise is the stimulation of bone formation. Gene therapy offers several potential advantages over other methods of osteoinduction and current research suggests that it may be a feasible treatment option for the orthopedic surgeon in the near future. This article reviews the basic concepts and strategies of gene therapy and evaluates the current research using gene therapy to induce bone formation and enhance healing.

Bone Marrow Cells↗