Seth C. Gamradt

Influence of BMPs on the Formation of Osteoblastic Lesions in Metastatic Prostate Cancer

The purpose of this study was to evaluate the role of BMPs on the formation of metastatic prostate cancer lesions to bone. Our results show that BMPs influence the development and progression of osteoblastic lesions and suggest that therapies that inhibit BMP activity may reduce the formation and progression of osteoblastic lesions.

Lentivirus-mediated gene transfer induces long-term transgene expression of BMP-2 in vitro and new bone formation in vivo

We examined the potential of ex vivo gene therapy to enhance bone repair using lentiviral vectors encoding either enhanced green fluorescent protein (EGFP) as a reporter gene or bone morphogenetic protein-2 (BMP-2) downstream of either the cytomegalovirus immediate early (CMV) promoter or the murine leukemia virus long terminal repeat (RhMLV) promoter derived from a murine retrovirus adapted to replicate in a rhesus macaque. In vitro, rat bone marrow stromal cells (BMSCs) transduced with Lenti-CMV-EGFP or Lenti-RhMLV-EGFP demonstrated over 90% transduction efficiency at 1 week and continued to demonstrate stable expression for 8 weeks. ELISA results demonstrated that lentivirus-mediated gene transfer into BMSCs induced stable BMP-2 production in vitro for 8 weeks. Increased EGFP and BMP-2 production was noted with the RhMLV promoter. In addition, we implanted BMSCs transduced with Lenti-RhMLV-BMP-2 into a muscle pouch in the hind limbs of severe combined immune deficient mice. Robust bone formation was noted in animals that received Lenti-RhMLV-BMP-2 cells at 3 weeks. These results demonstrate that lentiviral vectors expressing BMP-2 can induce long-term gene expression in vitro and new bone formation in vivo under the control of the RhMLV promoter. Prolonged gene expression may be advantageous when developing tissue engineering strategies to repair large bone defects.

Genetic modification of stem cells to enhance bone repair.

Orthopaedic surgeons are often faced with difficult bone loss problems. Conventional bone grafting is usually accomplished with autogenous iliac crest bone graft that provides osteogenic cells, osteoinductive growth factors, and an osteoconductive matrix. Cadaveric bone allograft and bone graft substitutes are inferior to autogenous bone graft because they fail to supply osteogenic cells or a significant amount of osteoinductive growth factors. Recombinant growth factors such as bone morphogenetic protein-2 and osteogenic protein-1 are currently in clinical use but these proteins require supraphysiologic dosing and considerable expense while failing to provide a sustained osteoinductive signal at the implantation site. Mesenchymal stem cells capable of differentiating into mesodermal tissues have been isolated and expanded in culture from several different sources including bone marrow, adipose tissue, and muscle. In the presence of appropriate growth factors these cells can differentiate into osteoblast lineage cells that will form bone in vitro and in vivo. Recent attention has focused on genetic modification of mesenchymal stem cells to both produce and respond to osteogenic growth factors with the goal of developing a tissue engineering strategy for bone repair. This review examines the current potential and limitations of these cellular systems for bone repair.

Perioperative complications of threaded cylindrical lumbar interbody fusion devices: anterior versus posterior approach.

Few data are available to evaluate approach-related differences in perioperative complications with lumbar interbody fusion devices. Complications occurring in the intraoperative and immediate postoperative period were identified and categorized for 31 consecutive posterior lumbar interbody fusions (PLIFs) and 88 consecutive anterior lumbar interbody fusions (ALIFs). In this study, all lumbar interbody fusions were conducted with threaded cylindrical devices as stand-alone internal fixation devices. Multivariate analysis was used to account for potential covariates and identify factors associated with an increased complication risk. Twenty-two percent of the patients had a perioperative complication. The relative risk of having a perioperative complication was 4.75 times higher for the PLIF group. All intraoperative complications occurred in the PLIF group. The relative risk of having a major postoperative complication was 6.8 times higher in the PLIF group than the ALIF group. Anterior approached patients tended to have visceral (ileus, 6%) and vascular (deep venous thrombosis, 2%) complications. In the posterior group, complications were neurologic and dura related (pseudomeningocele, 16%; epidural hematoma, 3%) and occurred most frequently in patients that had had previous posterior lumbar surgery (31% with major complication).

Demographic Trends in Arthroscopic SLAP Repair in the United States

Background: Treatment of superior labral anterior posterior (SLAP) tears remains controversial, particularly in older age groups. Repair, debridement, biceps tenodesis, tenotomy, and observation have been recommended depending on patient characteristics, but there have not been any large epidemiologic studies investigating treatment trends. Purpose: To investigate current trends in SLAP repair across time, gender, age, and regions in the United States. Study Design: Descriptive epidemiology study. Methods: Patients who underwent arthroscopic SLAP repair (Current Procedural Terminology [CPT] code 29807) were identified using a publicly available national database of insurance records (PearlDiver Patient Records Database) during years 2004 through 2009. Factors identified for each patient included gender, age group, and region in the United States. Logistic regression analysis and the chi-square test were used for statistical measures. Results: From 2004 to 2009 there were 25,574 cases of arthroscopic SLAP repair identified, of which 75% were male patients and 25% were female patients. There was a significant rise in cases of SLAP repair from 2004 to 2009 as the incidence of SLAP repair increased from 17.0 for every 10,000 patients with an orthopaedic International Classification of Diseases, Ninth Revision (ICD-9) or CPT code in 2004 to 28.1 in 2009 (P < .0001). Age analysis revealed the highest incidence in the 20-29–year (29.1 per 10,000) and 40-49–year (27.8 per 10,000) age groups. Men (37.3 per 10,000) had a significantly higher incidence of repairs than did women (10.7 per 10,000). The West (24.6 per 10,000) and South (24.4 per 10,000) regions also demonstrated a higher incidence than the Midwest (20.5 per 10,000) and Northeast (20.1 per 10,000) regions (P < .0001). Conclusion: Our analysis illustrates that surgeons are performing significantly more arthroscopic SLAP repairs each year. The highest incidence of repair is in the 20-29– and 40-49–year age groups, and a significant gender difference exists, with men having a threefold higher incidence of repair.

Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model

Prolonged systemic administration of corticosteroids causes osteoporosis and increased risk of fracture. Despite this well documented side effect of systemic corticosteroids, the effect of these compounds on fracture healing is not well defined. The goal of this study was to test the hypothesis that systemic corticosteroid therapy adversely affects fracture healing in a rabbit ulnar osteotomy model. Non-critical sized (1 mm) defects were created bilaterally in 18 adult female New Zealand White rabbits. Starting 2 months before operative intervention and continuing for 6 weeks during healing of the osteotomies, a subcutaneous dose of either sterile saline or prednisone (0.15 mg/kg) was administered daily. Serial radiographs of the forelimb were taken immediately postoperatively and weekly beginning the second week postoperatively. After killing at 6 weeks, only 3 of 20 limbs from animals treated with prednisone achieved radiographic union while 13 of 16 control limbs achieved union. The radiographic density of bone in the defect as well as callus size were greater in the control limbs than in the limbs from prednisone-treated animals. DEXA confirmed that the bone mineral content was lower in the ulnae of prednisone-treated rabbits both within the defect and in adjacent ulnar bone. Mechanical data indicated that osteotomies from rabbits chronically treated with prednisone were weaker than in controls. In this rabbit ulnar osteotomy model, chronic prednisone treatment clearly inhibited bone healing.

Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy.

A new class of parathyroid hormone-related protein (PTHrP) analogs has been developed that causes a rapid gain in both trabecular and cortical bone in models of osteopenia. This study investigates the efficacy of the PTHrP analog, RS-66271 ([MAP(1-10)]22-31 hPTHrP(1-34)-NH(2)), as systemic therapy for impaired bone healing in corticosteroid-treated rabbits. A 1 mm defect was created bilaterally in the ulnae of 30 rabbits. Delayed healing was induced by daily injections of prednisone (0.15 mg/kg) beginning 2 months prior to surgery and continuing until killing. Rabbits in the experimental group received daily subcutaneous injections of PTHrP analog RS-66271 (0.01 mg/kg) starting 1 day after surgery. Control animals received subcutaneous normal saline. At the 6 week timepoint, nine of ten ulnae from PTHrP-treated rabbits achieved radiographic union, whereas only two of ten limbs achieved union in control rabbits (p < 0.01). In a separate part of the study, 20 animals (10 control, 10 RS-66271-treated) were killed when radiographic union was achieved bilaterally. In this portion of the study, all limbs in animals treated with PTHrP achieved union by 6 weeks. In the control animals that were allowed to heal for 10 weeks, only 20% of the limbs achieved radiographic union. In addition, ulnae in the PTHrP-analog-treated rabbits showed greater radiographic intensity (20%-40%), larger callus area (209% anteroposterior view, 417% lateral view) (mean area on AP radiographs: control, = 387 +/- 276 mm(2); PTHrP analog, 1195 +/- 408 mm(2)), and greater stiffness (64%) and torque (87%) when compared with controls. RS-66271 was shown to be an effective therapy for preventing impaired bone healing caused by prednisone in a rabbit model.

Health-Related Quality of Life Outcomes Improve After Multilevel Surgery in Ambulatory Children With Cerebral Palsy

Background: Studies evaluating multilevel surgery to treat spastic deformity and functional deficits in cerebral palsy (CP) usually focus on data from instrumented gait analysis and clinical examination without examining functional and health-related quality of life (HRQOL) outcomes. Recently, outcome measures for well-being in children with a variety of musculoskeletal disorders have also been validated specifically for CP. Therefore, this study aimed to investigate the impact of multilevel surgery on the function and HRQOL in a group of ambulatory children with CP. Methods: In a multicenter prospective trial, 57 ambulatory children with CP, mean age 9.5 years, underwent multilevel soft tissue surgery to correct sagittal imbalance. Validated clinical outcome measures for HRQOL were administered preoperatively and postoperatively with an average follow-up time of 15.2 months. The functional and psychosocial components of the Pediatric Outcomes Data Collection Instrument (PODCI), Pediatric Quality of Life Questionnaire (PedsQL), and the Functional Assessment Questionnaire Walking Score were used. Results: Significant improvements in outcome scores occurred postoperatively in the following: PedsQL parent-total (17.6%; P < 0.001) and parent-physical sections (25.0%; P < 0.001), the Functional Assessment Questionnaire Walking Score (15.3%; P < 0.001), and the PODCI sections for transfers and basic mobility (15.8%; P < 0.001), sports and physical function (23.9%; P = 0.012), and global (12.9%; P < 0.001). Improvements also occurred in the PedsQL child-total (8.4%; P = 0.104) and child-physical sections (8.6%; P = 0.189), but these were not statistically significant. There were no significant changes in the PODCI parent-derived pain (−3.2%; P = 0.504) and happiness sections (1.9%; P = 0.645). Conclusions: Multilevel surgery in ambulatory patients with CP improves function and HRQOL. However, improved functional well-being does not imply improved psychosocial well-being, and patients and their families should be counseled accordingly. Level of Evidence: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.

Platelet Rich Plasma in Rotator Cuff Repair

Despite clinical success rates over 85%, persistent anatomic defects after rotator cuff repair are common and depend on the size of the tear repaired. The etiology of delayed or failed tendon to bone healing is multifactorial and biologic augmentation of a rotator cuff repair would be clinically desirable. Autogenous platelets contain many growth factors and are critical in the physiology of bone, soft tissue, and wound healing. Growth factors present in platelets include TGF-B, FGF, PDGF, EGF, and VEGF. Centrifugation techniques have been developed to create platelet rich plasma (PRP). These PRP preparations are designed to concentrate platelets and the growth factors they provide. PRP has been used to augment healing in various animal models as well as clinical situations in humans. This review examines the potential of using PRP to augment rotator cuff repair.

Arthroscopic Intratendinous Repair of the Delaminated Partial-Thickness Rotator Cuff Tear in Overhead Athletes

A distinct type of partial-thickness rotator cuff tear has been observed in overhead athletes, characterized by partial failure of the undersurface of the posterior supraspinatus and anterior infraspinatus tendons with intratendinous delamination. We present a technique of percutaneous intratendinous repair using nonabsorbable mattress sutures designed for the management of articular-side delaminated partial-thickness tears. After tear evaluation and preparation, the torn rotator cuff undersurface is held in a reduced position with a grasper through an anterolateral rotator interval portal while viewing intra-articularly. Two spinal needles are then placed percutaneously through the full thickness of the torn and intact rotator cuff. A polydioxanone suture is passed through each needle, retrieved out the anterior portal, and used to shuttle a single nonabsorbable No. 2 suture through the tissue, creating a mattress suture. Multiple mattress sutures can be placed as dictated by tear size and morphology, with suture retrieval and knot securing then proceeding in the subacromial space. We have adopted this approach with the goals of anatomically re-establishing the rotator cuff insertion and sealing the area of intratendinous delamination while preventing significant alteration to the anatomy of the rotator cuff insertion, which could lead to motion deficits, internal impingement, and potential tear recurrence.