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Biomedical subjects

M R Urist

Publications and source records attributed to M R Urist.

At least 19 recordsLinked to original sources
PubMed1992

Resistant nonunions and partial or complete segmental defects of long bones. Treatment with implants of a composite of human bone morphogenetic protein (BMP) and autolyzed, antigen-extracted, allogeneic (AAA) bone.

Twenty-five patients with resistant nonunions including partial or complete segmental defects were treated with a composite alloimplant of human bone morphogenetic protein (h-BMP) and autolyzed, antigen-free, allogeneic bone (AAA). The series consisted of 16 females and nine males; average age was 45 years. Preoperative symptoms averaged 30 months (range, five to 83 months); 22 of 25 patients had failed multiple attempts at electrical stimulation. Twenty-three of 25 patients had an average of three prior failed surgical attempts at union (range, one to ten). There were ten segmental defects with an average length of 4 cm (range, 2-9 cm). The composite implant was incorporated as an onlay in 15 extremities and as an inlay graft supported by internal fixation in ten extremities. Seven patients received supplementary autogeneic cancellous bone grafting. Average healing time was six months (range, three to 14 months). Average follow-up time was 21 months (range, five to 82 months). Functional results were rated as excellent, 14; good, five; and fair, five. One failed to unite because of a recurrent infection. Union was obtained in 24 of 25 patients. There were five failures of the original operation that required reoperations; union eventually occurred in four of five extremities by repeat composite grafting and replacement of the failed internal fixation. Bony union between host bone and the composite implant began at an average of eight weeks postoperatively. Present results indicate that h-BMP/AAA composite implants represent adjunctive treatment of difficult nonunions. The h-BMP/AAA composite implants may be implanted in either partial or complete segmental defects of long bones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Immune inhibition of repair of canine skull trephine defects implanted with partially purified bovine morphogenetic protein.

The healing of 14-mm trephine skull defects was observed in ten adult mongrel dogs. First and second set trephine operations were performed to determine whether xenogeneic bovine bone morphogenetic protein (bBMP) and associated bone matrix water-insoluble noncollagenous proteins (iNCP) incite an immunological humoral response inhibiting bone repair. The effects of immunization to BMP/iNCP were observed by serum radioimmunoassay, and by correlated roentgenographic and histological analysis of deposits of new bone. The first set implants of bBMP/iNCP induced 96% healing while the regeneration of the second set trephines was 34% less than the first set. The second set was associated with a significant increase in serum anti-BMP antibodies. While xenogeneic bBMP induced complete healing of trephine defects when implanted without previous immunization, and repair in response to a second set of bBMP/iNCP was always incomplete, further research with high purified recombinant BMP is required to measure immune effects in a statistically significant number of pure bred recipients.

Animals↗
PubMed1991

Allogenic bone and cartilage morphogenesis. Rat BMP in vivo and in vitro.

An allogenic aggregate of bone morphogenetic protein (BMP) and insoluble non-collagenous proteins (NCP) as well as a crude GuHCl extract were isolated from rats diaphyseal bones. Intramuscular implantation of 5 mg and 10 mg rat BMP/NCP in rats formed new ossicles, whereas 20 mg GuHCl extract failed to induce heterotopic bone formation. When 6 samples of inactivated rat bone matrix gelatin (BMG) were reconstituted with 0.75 mg of either BMP/NCP or GuHCl extract all 3 matrices reconstituted with BMP/NCP but only 1 out of 3 samples reconstituted with GuHCl extract induced heterotopic bone formation. Inactivated BMG alone did not show any osteoinductive activity. The small amount of BMP/NCP necessary for osteoinduction when recombined with inactivated BMG suggests that growth factors in bone matrix without inherent bone-forming activity enhance BMP activity. In vitro, connective tissue outgrowths of neonatal rat muscle on a substratum of inactivated rat BMG differentiated into cartilage in response to 0.05 microgram/ml, 0.5 microgram/ml and 5.0 micrograms/ml allogenic BMP/NCP added to the medium during the incubation period of 2 weeks. On day 14 of cultivation S35-sulphate incorporation into glycosaminoglycans (GAG) and H3-thymidine incorporation into DNA were measured, and the results related to the DNA content and the weight of the incubated muscle tissue, respectively. All doses of BMP/NCP increased GAG synthesis statistically significantly (p less than 0.05 to p less than 0.001). In contrast to that, DNA synthesis rate was not influenced by BMP/NCP. This suggests that GAG synthesis was not caused by cell proliferation but by cell differentiation.

Abdominal Muscles↗
PubMed1991

Induced bone development in transplants of fresh human pseudomalignant heterotopic ossification tissue in athymic nude mice.

Biopsy specimens of mature trabecular bone from tumors of two typical cases of pseudomalignant heterotopic ossification (PHO; myositis ossificans circumscripta) were transplanted into athymic nude mice. Specimens of normal metaphyseal bone in adjacent areas were also transplanted in the contralateral hindquarter muscles for controls. By seven days, control bone transplants were necrotic and enveloped in granulation tissues whereas PHO transplants were surrounded by proliferating connective tissue derived from the host-bed muscle tissues. In the intervals from 14 and 21 days, the PHO transplants showed vascular and hypertrophied connective-tissue proliferation with appositional deposits of new bone. The microscopic features of the new bone suggested that it was of mouse host-bed origin because the new bone from Case 1, a female, showed nuclei without sex chromatin. The quantities of new bone were measured by correlated histomorphometric and computer image analysis of microradiographs. Little or no cartilage development was noted at any stage. The normal control trabecular bone tissue was slowly resorbed by macrophages and mononuclear phagocytes; multinucleated giant cells were few and relatively small. Except in one questionably small area of one transplant, nontumorous undemineralized normal human bone failed to induce bone formation within the 28-day period of observation. The quantity of new bone formed in athymic mice in response to implants of PHO, estimated from equivalent quantities of bone developed from implants of lyophilized matrix-free bone morphogenetic protein (BMP) was about 1 microgram/g of wet PHO tumor weight. Although circumstantial evidence implicates BMP in the pathogenesis of heterotopic ossification, more research should be directed toward regional and systemic factors inhibiting bone development in normal and abnormal conditions, including malignant bone tumors.

Adult↗
PubMed1990

Bone morphogenetic protein-mediated interaction of periosteum and diaphysis. Citric acid and other factors influencing the generation of parosteal bone.

In rabbits, after long-bone growth is complete and the cambium layer regresses, mesenchymal-type cells with embryonic potential (competence) for bone development persist in the adventitial layer of periosteum. These cells are not determined osteoprogenitor cells (stem cells) because bone tissue differentiation does not occur when adult periosteum is transplanted into a heterotopic site. In this respect, adventitial cells differ from bone marrow stroma cells. In a parosteal orthotopic site in the space between the adult periosteum and diaphysis, implants of bone morphogenetic protein (BMP) and associated noncollagenous proteins (BMP/NCP) induce adventitia and adjacent muscle connective-tissue-derived cells to switch from a fibrogenetic to a chondroosteoprogenetic pattern of bone development. The quantity of induced bone is proportional to the dose of BMP/NCP in the range from 10 to 50 mg; immature rabbits produced larger deposits than mature rabbits in response to BMP/NCP. Preoperative local intramuscular injections of citric, edetic, or hyaluronic acids in specified concentrations markedly enhanced subperiosteal BMP/NCP-induced bone formation. The quantity of bovine or human BMP/NCP-induced bone formation in rabbits is also increased by very low-dose immunosuppression but not by bone mineral, tricalcium phosphate ceramic, inorganic calcium salts, or various space-occupying, unspecific chemical irritants. Although composities of BMP/NCP and allogeneic rabbit tendon collagen increased the quantity of bone in a parosteal site, in a heterotopic site the composite failed to induce bone formation. In a parosteal site, the conditions permitting BMP/NCP-induced bone formation develop, and the end product of the morphogenetic response is a duplicate diaphysis. How BMP reactivates the morphogenetic process in postfetal mesenchymal-type adventitial cells persisting in adult periosteum (including adjacent muscle attachments) is not known.

Animals↗
PubMed1990

Distal metaphyseal tibial nonunion. Deformity and bone loss treated by open reduction, internal fixation, and human bone morphogenetic protein (hBMP).

Four patients with severely deformed nonunions of the distal end of the tibia failed to respond to standard surgical methods and were successfully treated as follows: debridement of fibrous tissue, sequestrectomy, correction of angulatory deformities, internal stabilization, and implantation of human bone morphogenetic protein (hBMP). After resection of the sequestra, all four patients had significant bone defects of the anterior tibial cortex extending to the ankle joint. The average number of failed previous surgical procedures was 5.8. The average patient age was 35.3 years. The intervals of nonunion averaged 24.8 months. In two patients, the hBMP, including other low molecular weight bone matrix noncollagenous proteins (hBMP/NCP), was implanted across the fracture site in polylactic-polyglycollic acid strips (1 X 13 cm) as an onlay graft. In one patient, the BMP was implanted in the fracture gap in absorbable gelatin (No. 5 capsules). In another patient, the BMP/NCP was also implanted in the form of a composite of cortical allogeneic bone in addition to a capsule of BMP/NCP. In all four cases, alignment was restored and the bone ends were stabilized with internal fixation. Preoperatively, the ankle joints were ankylosed and painful. Healed fractures and functional ankle joints were observed in three of four patients at an average of 4.4 months. In one patient, the fracture healed but the joint remained ankylosed. Although a randomized double-blind consecutive series of matched cases is necessary to prove the efficacy of hBMP, implants of hBMP combined with skillful surgical treatment are under investigation in the interim as an alternative to amputation.

Adult↗
PubMed1989

Bovine tooth-derived bone morphogenetic protein.

Eight groups of dental tissues were mechanically dissected from the mandibles of one-year-old steers; they were then defatted and decalcified in HCl. The noncollagenous proteins were extracted with various solvents from collections of tissue and bio-assayed for osteo-inductive activity. Collectively, the hard tissue (dentin, enamel, and cementum) noncollagenous proteins were fractionated by molecular sieve chromatography, hydroxyapatite affinity chromatography, and ion exchange chromatography. Osteo-inductive activity of each protein fraction was determined by implantation in the quadriceps muscle pouch of mice. The quantity of bone was measured by computerized image analysis. From 71% to 83% of 41 implants of dental hard tissues induced bone formation. The quantity of bone was greater from unerupted than from erupted teeth. Dental soft tissues that had no osteo-inductive activity were rich in a 14-kDa protein, presumably matrix gamma-carboxyglutamic acid-rich proteins. Proteins with Mr of from 15 to 28 kDa were associated with osteo-inductive activity. Components with Mr greater than 28 kDa had no activity. These observations suggest that bovine teeth have a selection of osteo-inductive proteins that is comparable in range of MW to bovine bone morphogenetic protein.

Animals↗
PubMed1989

Autogeneic cancellous bone grafts in extensive segmental ulnar defects in dogs. Effects of xenogeneic bovine bone morphogenetic protein without and with interposition of soft tissues and interruption of blood supply.

Xenogeneic (bovine) bone morphogenetic protein (bBMP) and associated insoluble noncollagenous proteins (NCP) were implanted in inbred adult beagle dogs with 3-4 cm diaphyseal defects in the ulna. Defects were stabilized with internal plate fixation, and the control defects were not stabilized. The defects were implanted with either autogeneic cancellous bone grafts (ACG), bBMP/NCP, or a composite of ACG and bBMP/NCP. Of the plated ulnae, 18 of 19 ACG controls restored bone continuity; six of seven defects healed under the influence of bBMP/NCP plus ACG. Two of four defects with bBMP/NCP plus ACG healed and two were filled with osseous tissue, but fibrous tissue developed at one or both bone ends. Eight of nine defects implanted with bBMP/NCP capsules alone were repaired with fibrous tissue only. Of the nonplated defects, four were implanted with bBMP/NCP plus ACG and only one regenerated; three of four showed hypertrophic bone growth around a pseudarthrosis. Of six nonplated defects implanted with bBMP/NCP without ACG, all developed atrophic bone ends and fibrous tissue repair. Thus, to restore continuity of large segmental defects three times greater than the critical size for spontaneous regeneration, xenogeneic bBMP/NCP failed to induce bone regeneration in dogs. To exclude cell-mediated immune reactions and soft-tissue ingrowth, one defect was bridged with a polytetrafluoroethylene semipermeable tube (pore size 0.45 micron) containing implants of bBMP/NCP. In response to bBMP/NCP, cells from the host bone ends produced ossicles of induced woven bone formation. The observation that bBMP/NCP induced bone formation across the defect inside of semipermeable cylindrical chambers suggests that the experiments on bone defects larger than the critical size for spontaneous repair should be repeated with: (1) allogeneic dog BMP/NCP; (2) semipermeable cylinders to protect against muscle interposition; (3) compartment angiograms to evaluate blood supply; (4) treatment of the recipient with immunosuppressants and immunostaining to observe the concentration gradient of BMP; and (5) histologic observations on the first three days after implantation to evaluate cell-mediated immune barriers to the response of BMP.

Animals↗
PubMed1989

A 37-year follow-up evaluation of multiple-stage femur and tibia lengthening in dyschondroplasia (enchondromatosis) with a net gain of 23.3 centimeters.

This case report presents the rare combination of circumstances of a child with (a) dyschondroplasia (enchondromatosis) limited to all the major epiphyseal plates of one lower extremity, (b) unusual capacity to cooperate, and (c) parents who refused permission to treat the limb by amputation but allowed the child to participate in a long-term clinical experiment. In dyschondroplasia (Ollier's disease), the long bones grow in diameter but not in length. In this condition, it was possible (by fasciotomy, osteotomy, and interposition of wedge blocks or hemicylindrical bone implants (stabilized by an intramedullary rod) to lengthen the leg 23.3 cm in ten stages, during the period between five and 14 years of age. With the additional procedure of epiphyseal arrest of the contralateral distal end of the femur at age 11, the eventual correction of discrepancy in leg length was 25.6 cm. Intraoperative and postoperative skin temperature recordings, toe plethysmography, and electromyography show that there were no deleterious changes in the circulatory or neurological functions of the extremity.

Adult↗
PubMed1989

Augmentation of spinal fusion with bone morphogenetic protein in dogs.

Bone morphogenetic protein (BMP) induces mesenchymal cells to differentiate into cartilage and bone. To investigate the action of BMP on the growth of host bed-derived bone in experimental spinal fusions, posterior intervertebral spinal fusions of the lower thoracic spine were performed in 13 mature mongrel dogs. Four different fusion methods were used at single intervertebral levels within each dog. Three levels in each dog were used as controls for the BMP level. The spinal columns were examined by radiohistomorphometric methods at three weeks, six weeks, and 12 weeks and showed the BMP level to have two to three times more new bone than control levels. At the BMP level, an increase in the amount of new bone was observed in the interval from three to 12 weeks, in contrast to a decrease seen at the control levels. Fusion was present in five of seven of the BMP levels compared with zero of seven, one of seven, and two of seven in the control levels. The BMP level exhibited an increased number and volume of areas of de novo cartilage and woven bone formation at all time intervals compared to all control levels. The polylactic acid polymer carrier was not resorbed and partially retained in the fusion site. The preliminary observations suggest that BMP may serve as a useful adjunct in spinal fusions, but research is required to find a rapidly degradable delivery system. The objective of BMP research is to augment the host bed capacity for bone generation and regeneration and to spare children and adults the pain and complications involved in removing excessive volumes of iliac crest bone grafts.

Animals↗
PubMed1989

Distal metaphyseal tibial nonunions associated with significant bowing deformity and cortical bone loss: treatment with human bone morphogenetic protein (h-BMP) and internal fixation.

Distal tibial metaphyseal nonunions with significant posterior bowing deformities are extremely difficult to manage and may require the use of additional healing factors to achieve union. Four patients with complex multiple failed surgically treated distal metaphyseal nonunions were treated with debridement of the nonunion, correction of deformities, internal stabilization, and augmentation with human bone morphogenetic protein implants (h-BMP). All patients had, following resection of the anterior cortical sequestrum, a significant cortical defect extending from a level proximal to the ankle joint to the distal tibial metaphysis. The average number of failed previous surgical procedures were 5.8 and average age was 35.3 years. Symptomatic nonunion averaged 24.8 months. All patients received h-BMP combined with insoluble noncollagenous proteins (iNCP) either in a delivery form of coated polylactic polyglycolic acid strips (1 x 13 cm.) or in gelatin capsules. The h-BMP/iNCP implants were placed within the anterior cortical defects in contact with the residual distal metaphyseal bone. All nonunions were stabilized with internal fixation. Ankle motion was difficult to record preoperatively but good to very good ankle function was obtained at final follow-up evaluation in three of four patients. All fractures healed without further surgical treatment at an average of 4.4 months. h-BMP/iNCP protein implants were felt to be of benefit in the healing of these difficult fracture problems.

Adult↗
PubMed1988

Growth factors, mitogens, cytokines, and bone morphogenetic protein in induced chondrogenesis in tissue culture.

Connective tissue outgrowths of neonatal muscle onto a substratum of bone matrix differentiate into cartilage in response to a bone morphogenetic protein (BMP). The BMP can be separated from bone matrix by extraction with 4 M guanidine hydrochloride (GuHCl) or degraded in situ by endogenous proteolytic enzymes to deactivate the matrix. Rat triceps muscle was minced in a suspension of noncollagenous bone matrix proteins including BMP (BMP/NCP) in culture medium. To investigate the possible synergistic interactions in induced chondrogenesis, six biosynthesized, highly purified growth factors were similarly added to the culture alone or in combination with BMP. Human interleukin-1 (IL-1) and Forskolin were also introduced to test the effects on BMP/NCP-induced chondrogenesis. On Day 14 of cultivation, [3H]thymidine incorporation into DNA and [35S]sulfate incorporation into glycosaminoglycans (GAG) were measured, and the values were expressed as percentages of the control. The quantity of induced cartilage formation was estimated by a histomorphometric scoring system. Under the influence of BMP/NCP, cultures grew on deactivated matrix, incorporated 55% more [3H]thymidine into DNA, incorporated 115% more [35S]sulfate into GAG than control cultures, and differentiated into cartilage. Without BMP/NCP, growth factors, IL-1, and Forskolin did not produce a comparable incorporation of either [3H]thymidine or [35S]sulfate, and they induced differentiation of fibrous tissue only. In the presence of BMP/NCP, cartilage developed in nearly all cultures. When the media were supplemented with growth factors, measurable increases in uptake of [3H]thymidine occurred with human epidermal growth factor (h-EGF), insulin-like growth factor-1 (IGF-1), nerve growth factor (NGF), transforming growth factor-beta (TGF-beta), bovine acidic fibroblast growth factor (baFGF), IL-1, bovine basic fibroblast growth factor (bbFGF), and Forskolin. Measurable increases in uptake of [35S]sulfate into GAG occurred with IL-1, baFGF, TGF-beta, h-EGF, IGF-1, bbFGF, NGF, and Forskolin. Synergistic interaction with BMP was considered when the quantity of cartilage developed (on a scale of 0-12 scores) in excess of the quantity of Score 4 induced by BMP/NCP alone. A cytokine, IL-1, had the greatest effect (Score 9). TGF-beta (Score 7), baFGF (Score 6), and NGF (Score 6) had relatively little effect. h-EGF, IGF-1, bbFGF, and Forskolin had no effect on cartilage development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Repair of segmental defects of the tibia with cancellous bone grafts augmented with human bone morphogenetic protein. A preliminary report.

Human bone morphogenetic protein (hBMP) is a bone cell differentiation-inducing factor. Six patients with traumatic segmental three- to 17-cm tibial defects developed solid union by implantation of hBMP and autogeneic cancellous grafts and stabilization. There were no allergic, infectious, or surgical complications. If hBMP augmentation in biodegradable delivery systems can be established by a prospective, randomized, double-blind investigation, the incidence of successful bone graft operations for treatment of large segmental defects would be measurably improved.

Adult↗
PubMed1988

Quantitative computation of induced heterotopic bone formation by an image analysis system.

The formation of heterotopic bone (HO) is an unsolved problem and occurs in response to a variety of conditions including muscle contusions, injuries, surgical procedures, and burns. A sensitive method for quantification of HO would be valuable for experimental work and research on bone morphogenetic protein (BMP). The hardware and software used in an image analysis system are presented. This system provides a rapid and highly accurate method for determining the amount of HO in a muscle. Using the mouse thigh pouch as an experimental system, this method demonstrated that quantities of new bone were formed in direct proportion to the amount of BMP/NCP implanted. This system can be used for measuring HO on roentgenograms or any other image, including computed tomographic (CT) scans, magnetic resonance imaging (MRI), and autoradiograms.

Animals↗
PubMed1988

Induction of callus formation by implants of bone morphogenetic protein and associated bone matrix noncollagenous proteins.

Callus formation in the periosteal bone interface in response to bone morphogenetic protein (BMP) and associated bone matrix noncollagenous proteins (BMP/NCP) was investigated in mature adult rabbits. For controls byproducts of BMP/NCP purification, bone marrow, eight nonskeletal tissues, purified matrix gamma-carboxyglutamic acid-rich protein (MGP), and a composite of BMP/NCP and polylactic-polyglycolic acid polymer (PLA/PGA) were also implanted in the periosteal bone interface. Quantitative microcomputer image analysis and histologic studies were performed three weeks after the implantation. BMP/NCP and bone marrow or BMP/NCP implanted over a single drill hole into the marrow cavity produced three times more new bone than the bone marrow alone. BMP/NCP alone produced twice as much new bone as bone marrow alone. Control implants of bovine serum albumin or purified MGP produced no new bone. Autogeneic minced muscle and ten nonskeletal tissue controls produced little or no bone formation. Even at one-fifth of the dose of BMP/NCP, a composite of PLA/PGA incorporating BMP/NCP showed almost the same amount of new bone as BMP alone. Histologically, the response to BMP/NCP consisted of an external callus of calcifying cartilage and woven bone. The response to subperiosteal implants of BMP/NCP or BMP/NCP with bone marrow or with minced muscle occurred with the same sequence of developmental events as seen either in embryonic skeletogenesis or in fracture callus.

Animals↗
PubMed1988

Experimental heterotopic bone formation induced by bone morphogenetic protein and recombinant human interleukin-1B.

The object of this research is to investigate the influence of interleukin-1 (IL-1) on heterotopic ossification (HO) induced by bone morphogenetic protein (BMP). Adult mice were implanted with doses of 1, 2, 5, and 10 mg of BMP. Several local injections of 10, 100, and 1000 units of a recombinant IL-1 beta (rIL-1 beta) were administered during the morphogenetic phase of development, starting a day before operation until one week postoperation. While IL-1 acts principally on cell proliferation, BMP primarily shows cell differentiation in the form of HO. BMP-induced HO is quantitated by computer X-ray image scanning, bone ash weight, alkaline phosphatase activity, and histological methods. The area of human BMP-induced HO was completely abolished by injections of polyclonal and monoclonal anti-IL-1 antibody. Monoclonal antibody did not cross-react with the same efficiency as polyclonal with bovine BMP. Polyclonal anti-IL-1 antibody totally neutralizes bovine BMP activity. IL-1-enhanced BMP induced HO and increased the volume of new bone in a statistically significant increment.

Alkaline Phosphatase↗