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Howard Seeherman

Publications and source records attributed to Howard Seeherman.

8 recordsLinked to original sources
PubMed2006

rhBMP-2/calcium phosphate matrix accelerates osteotomy-site healing in a nonhuman primate model at multiple treatment times and concentrations.

BACKGROUND: While recombinant human bone morphogenetic protein-2 (rhBMP-2) administered in a calcium phosphate cement accelerates osteotomy-site healing in animal models when administered three hours after surgery, definitive fracture treatment is often delayed. The present study evaluated the ability of rhBMP-2, administered in a new particulating calcium phosphate matrix, to accelerate nonhuman primate fibular osteotomy-site healing following treatment at multiple treatment times and concentrations. METHODS: The ability of 1.5-mg/mL rhBMP-2/calcium phosphate matrix to accelerate osteotomy-site healing when administered three hours, one day, one week, or two weeks after surgery was first evaluated with use of bilateral proximal and distal fibular osteotomy sites in adult male monkeys. In a second study, the healing of osteotomy sites that had been treated with the administration of calcium phosphate matrix alone and with different concentrations of rhBMP-2/calcium phosphate matrix (0.5 mg/mL, 1.5 mg/mL, or 4.5 mg/mL) seven days after surgery was compared with that of contralateral, untreated osteotomy sites. In a third study, the histologic progression of osteotomy-site healing following treatment with 1.5-mg/mL rhBMP-2/calcium phosphate matrix or calcium phosphate matrix alone, administered three hours or one week after surgery to the osteotomy site, was assessed at multiple time points for as long as twenty-four months after surgery. RESULTS: Radiographs demonstrated increased callus area and more rapid healing in response to 1.5-mg/mL rhBMP-2/calcium phosphate matrix administered over the range of treatment times after surgery as compared with the findings of previous reports on untreated osteotomy sites. Bone formation appeared at the osteotomy sites sooner following treatment at one and two weeks as compared with the findings at the earlier time-points. Scintigraphic imaging at one day and one week after surgery showed prolonged retention of rhBMP-2 at the osteotomy site following an initial burst release. In the second study, radiographic, peripheral quantitative computed tomographic, biomechanical, and microscopic evaluation demonstrated that administration of 1.5 and 4.5-mg/mL rhBMP-2/calcium phosphate matrix one week after surgery accelerated osteotomy-site healing by 40% to 50% compared with the findings in untreated controls. The magnitude of acceleration was less in response to 0.5-mg/mL rhBMP-2/calcium phosphate matrix, and calcium phosphate matrix alone did not accelerate osteotomy-site healing. Histological evaluation indicated that an increased cellular infiltrate and increased direct bone formation contributed to the accelerated osteotomy-site healing following administration of rhBMP-2/calcium phosphate matrix at one week compared with three hours after surgery. CONCLUSIONS: A single percutaneous injection of rhBMP-2/calcium phosphate matrix accelerated healing in nonhuman primate fibular osteotomy sites over a wide range of treatment times. Efficacy was optimized in association with the administration of 1.5-mg/mL rhBMP-2/calcium phosphate matrix. Delaying treatment for one week further accelerated healing because of an increase in the number of responding cells and an increase in direct bone formation.

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PubMed2005

Delivery of bone morphogenetic proteins for orthopedic tissue regeneration.

Carriers for bone morphogenetic proteins (BMPs) are used to increase retention of these factors at orthopedic treatment sites for a sufficient period of time to allow regenerative tissue forming cells to migrate to the area of injury and to proliferate and differentiate. Carriers can also serve as a matrix for cell infiltration while maintaining the volume in which repair tissue can form. Carriers have to be biocompatible and are often required to be bioresorbable. Carriers also have to be easily, and cost-effectively, manufactured for large-scale production, conveniently sterilized and have appropriate storage requirements and stability. All of these processes have to be approvable by regulatory agencies. The four major categories of BMP carrier materials include natural polymers, inorganic materials, synthetic polymers, composites of these materials. Autograft or allograft carriers have also used. Carrier configurations range from simple depot delivery systems to more complex systems mimicking the extracellular matrix structure and function. Bone regenerative carriers include depot delivery systems for fracture repair, three-dimensional polymer or ceramic composites for segmental repairs and spine fusion and metal or metal/ceramic composites for augmenting implant integration. Tendon/ligament regenerative carriers range from depot delivery systems to three-dimensional carriers that are either randomly oriented or linearly oriented to improve regenerative tissue alignment. Cartilage regenerative systems generally require three-dimensional matrices and often incorporate cells in addition to factors to augment the repair. Alternative BMP delivery systems include viral vectors, genetically altered cells, conjugated factors and small molecules.

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PubMed2003

The efficacy of BMP-2 to induce bone ingrowth in a total hip replacement model.

The purpose of this canine total hip arthroplasty (THA) study was fourfold: (1) to quantify the efficacy of rhBMP-2 in a carrier (alphaBSM) versus alphaBSM alone, and versus untreated controls to induce bone formation across a defect between a porous acetabular component and host bone; (2) to quantify whether rhBMP-2/alphaBSM improves bone growth into the porous surface beneath that defect; (3) to quantify the efficacy of rhBMP-2/alphaBSM in inducing bone ingrowth into the porous layer at points of intimate bone-implant contact; and (4) to determine whether rhBMP-2/alphaBSM placed in the lateral uncovered aspect of the porous acetabular component promotes de novo bone formation. Fifteen dogs were sacrificed 12 weeks after uncemented THA. Five dogs received rhBMP-2/alphaBSM, five dogs received alphaBSM, and five dogs were controls. In contrast to the controls in which no bone filled the defect, the rhBMP-2/alphaBSM induced defect filling and full bone formation in the underlying porous coating. The alphaBSM produced an intermediary response. However, no increase in new bone formation occurred at sites of intimate bone porous surface contact. Recombinant bone morphogenetic protein-2/alphaBSM promoted defect filling and bone ingrowth into the porous coating beneath the defect region, both of potential value in future total joint replacement surgery.

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PubMed2003

The safety and utility of recombinant human bone morphogenetic protein-2 for cranial procedures in a nonhuman primate model.

OBJECT: The goal of this study was to evaluate the safety and efficacy of recombinant human bone morphogenetic protein 2 (rhBMP-2) in cranial applications. METHODS: Critical-sized calvarial defects were created bilaterally in four rhesus monkeys, and bilateral rectangular bone flaps were created in six others. Control and rhBMP-2-treated sides were randomly chosen for each animal, and an absorbable collagen sponge was used to deliver the growth factor. Over a 6-month period postoperatively, the animals were serially evaluated for bone healing and adverse BMP-related consequences by using the following methods: computerized tomography (CT) scanning, magnetic resonance (MR) imaging, electroencephalography, histological investigations, and cerebrospinal fluid (CSF) analysis. The critical-sized defects for the rhBMP-2-treated and control sides attained 71 +/- 12% and 28 +/- 11% closure, respectively (four animals; p = 0.04). The CT scans demonstrated that the bone flaps treated with rhBMP-2 had complete osteointegration in five of six animals, whereas scans of the untreated bone flaps demonstrated uniformly poor osteointegration with the intact skull. Histological analysis confirmed well-formed bridges of bone on the rhBMP-2-treated sides. No epileptogenic activity was detected in any of the animals, and MR imaging revealed no evidence of adverse effects on the brain parenchyma. Meningitic irritation was not found on postoperative CSF sample analysis. CONCLUSIONS: Treatment of bone flaps and critical-sized cranial defects with rhBMP-2 leads to improved bone formation and osteointegration in nonhuman primates. Initial evaluation of rhBMP-2 appears to indicate a good safety profile for use in cranial procedures in primates.

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PubMed2002

Bone morphogenetic protein delivery systems.

STUDY DESIGN: A review was conducted. OBJECTIVES: To review the rationale for the use of carrier systems to deliver bone morphogenetic proteins to sites of orthopedic repair, and to discuss commonly used carriers. SUMMARY OF BACKGROUND DATA: Carriers for bone morphogenetic protein in spine fusion are used to increase the retention of these osteogenic factors at the treatment site, and to serve as an osteoconductive matrix for bone forming cells while maintaining a space or volume in which bone formation can occur. METHODS: The literature is reviewed and discussed. RESULTS: Although bone morphogenetic proteins can induce bone formation when delivered in formulation buffer in small animal models, carriers often are used in larger animal models and human clinical trials to maintain the concentration of osteogenic factors at the treatment site for a sufficient period to allow bone-forming cells to migrate to the area of injury and to proliferate and differentiate. For spine fusion, carriers also are required to serve as an osteoconductive matrix for bone-forming cells while maintaining a space or volume in which bone formation can occur. Four major categories of carrier materials are used for osteogenic factor delivery: inorganic materials, synthetic polymers, natural polymers, and composites of the first three materials. In addition, allograft bone has been used to deliver osteogenic factors to the site of orthopedic repairs. The efficacy of osteogenic carrier combinations often is site specific and species specific. The requirement for supraphysiologic concentrations of osteogenic factors may be related to the ability of the delivery system to increase the retention time at the treatment site and overcome tight regulation of these factors by their inhibitors. Dose escalation in large animal models also may be related to a decrease in the number of responding cells and a slower rate of bone formation. New delivery systems being evaluated include depot delivery systems, viral vector systems, conjugated osteogenic factor delivery systems, and oral small molecule targets. CONCLUSIONS: Delivery systems play an important role in the use of osteogenic factors to augment spine fusions and other orthopedic repairs.

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PubMed2002

Retention of 125I-labeled recombinant human bone morphogenetic protein-2 by biphasic calcium phosphate or a composite sponge in a rabbit posterolateral spine arthrodesis model.

The purpose of this study was to characterize the retention kinetics of recombinant human bone morphogenetic protein-2 (rhBMP-2) applied to two calcium-based delivery matrices. Biphasic calcium phosphate (BCP) and a composite containing BCP in an absorbable collagen sponge (BCP/ACS) were evaluated using a spinal fusion model in rabbits. rhBMP-2 labeled with radioactive iodine (125I) was used as a tracer to assess in vivo retention of rhBMP-2 in the presence of these materials (nine animals per material studied). Over a 36 day study period, animals were assessed for the following: percent administered dose retained at the implant site as measured by scintigraphic imaging (counting) with a gamma camera (all animals), radiography of the implant site (all animals), radioactivity in blood and plasma (all animals), and radioactivity in the urine and feces (three animals for each material). Radioactivity data were corrected for the decay of 125I and the attenuation between the implant in vivo and the gamma camera. Differences observed between the two materials for the area under the retention vs. time profile (AUC; 988%*day for BCP vs. 1070%*day for BCP/ACS, p = 0.57) and the mean residence time (MRT; 10.2 days for BCP vs. 7.6 days for BCP/ACS, p = 0.06) were not statistically significant. Initial retention/incorporation of rhBMP-2 was slightly higher for rhBMP-2/BCP/ACS than for rhBMP-2/BCP (96.8% vs. 86.0%, p < 0.05). Animals receiving rhBMP-2/BCP showed a longer terminal retention half-life (t1/2) than did those receiving rhBMP-2/BCP/ACS (7.5 vs. 4.5 days, p < 0.05). The urinary radioactivity recovery data supported the data obtained by scintigraphy. Over the 36 day collection period, essentially complete recovery of radioactivity (dose) in urine was observed for rhBMP-2/BCP and rhBMP-2/BCP/ACS and the majority of the radioactivity (approximately 95%) was soluble in trichloroacetic acid, suggesting extensive catabolism of rhBMP-2 before renal excretion. Fecal recovery of radioactivity was low, approximately 2-3%. In conclusion, rhBMP-2 was retained at the implant site when delivered with either BCP or BCP/ACS based on mean residence time and area under the retention curve vs. time profile. Use of these matrices resulted in detectable rhBMP-2 levels at the surgical site for over a week in contrast to data reported with several other matrices that lasted less time. Systemic catabolism and elimination of the rhBMP-2 was extensive and systemic presence of the protein was negligible.

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PubMedDate not supplied

Mandibular reconstruction of a partial hemimandibulectomy in a dog with severe malocclusion.

OBJECTIVE: To report treatment of severe mandibular malocclusion (after left partial hemimandibulectomy, approximately 7 cm gap). STUDY DESIGN: Clinical report. ANIMALS: A 14-month-old golden retriever. METHODS: After corrective osteotomy of the right horizontal mandibular ramus, normal occlusion was reestablished and temporarily maintained while both mandibles were stabilized by miniplates on the lateral alveolar surface spanning the bilateral mandibular defects (right=1.5 cm, left=7 cm). A fenestrated, monocortical rib graft was positioned beneath the left gingival surface to protect the synthetic graft, which was secured to the miniplate. A mandibular reconstruction plate (right) and a locking mandibular reconstruction plate (left) were secured to the ventral borders of the mandibles. Recombinant bone morphogenetic protein-2 delivered in collagen tricalcium phosphate sponges (rhBMP-2 collagen-TCP sponge) was inserted into both mandibular defects. RESULTS: New bone formation was identified at 3 months and bony remodeling was evident at recheck examinations up to 4 years. Scintigraphy (6 months, 1 year) confirmed graft revascularization and viability. Bone collected (1 year) from the left defect site had robust new bone formation and evidence of continued remodeling. Only minor complications were encountered during the postoperative period and were easily resolved. CONCLUSIONS: Reconstruction of a large mandibular defect was facilitated by use of an osteoinductive factor (rhBMP-2 collagen-TCP sponge) as a graft substitute. CLINICAL RELEVANCE: One-step salvage and reconstruction facilitated by use of an osteoinductive factor, as a graft substitute, may be an alternative strategy for repair of large mandibular defects.

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