Biomedical subjects
Publications and source records attributed to G A Finerman.
This report illustrates the use of three-dimensional imaging techniques to solve a difficult reconstruction problem of the hip. Custom prosthetic components manufactured by a computer-assisted design process are used in this procedure.
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.
Twelve patients with intractable nonunions of the femoral diaphyseal or metaphyseal-diaphyseal shaft were successfully treated by a combination of internal fixation and implants of human bone morphogenetic protein (h-BMP). There was an average of 4.3 surgical procedures per patient attempting union prior to h-BMP implantation. Union was obtained in 11 of 12 patients and in one patient with a repeat stabilization and implantation of h-BMP. Four patients received autogeneic cancellous bone graft and four patients received allogeneic bone grafts. The BMP implant was prepared in the form of an aggregate of h-BMP and bone matrix water-insoluble noncollagenous proteins (h-BMP/iNCP). Fifty to 100 mg of h-BMP/iNCP was either implanted in the fracture gap in ultra thin gelatin capsules, or incorporated in a strip of polylactic/polyglycolic acid copolymer (PLA/PGA) and placed as an onlay across the fracture gap. The average time to union was 4.7 months. Further clinical investigations are planned as a series of matched cases with and without BMP augmentation in order to distinguish h-BMP effects from new or improved methods of fracture fixation combined with autogeneic cancellous bone grafts.
Pigmented villonodular synovitis (PVNS) of the knee joint remains a difficult and elusive entity to define and characterize. This entity most often appears in the young adult knee with nonspecific clinical features, including a painful range of motion and perhaps a sensation of locking. Detection and diagnosis of this localized soft-tissue mass are difficult because plain roentgenograms may be totally within normal limits. The case of a 21-year-old woman illustrates the use of magnetic resonance imaging (MRI) as an effective technique to define and characterize PVNS. Advantages of MRI include high-resolution/high-contrast multiplanar sections that depict bone, marrow, ligaments and tendons, fat, menisci, and articular cartilage in one image. In addition, MRI is noninvasive and requires no ionized radiation. MRI is an excellent clinical tool for the evaluation of intraarticular tumors of the knee joint.
Beta tricalcium phosphate (TCP) was employed as a nonimmunogenic biodegradable delivery system for bovine bone morphogenetic protein (BMP). A BMP/TCP composite was implanted in adult dogs with skull trephine defects of a critical size of 1.4 cm that would otherwise remain unhealed in the lifetime of the individual. BMP/TCP implants induced 91%-100% incorporation by deposits of new bone. In comparison, control implants of TCP impregnated with bovine serum albumin (BSA/TCP) induced 0%-8% incorporation, or only marginal host bed reactive bone formation. The retention of unabsorbed TCP in the host bone four months after implantation suggests that further research should be encouraged to obtain a formulation of sintered calcium phosphate that could be resorbed more rapidly and in the process more completely replaced by bone.
Twenty-six severely deformed patients with prosthetic arthroplasty of both hips and both knees because of rheumatoid arthritis (16), juvenile rheumatoid arthritis (6), ankylosing spondylitis (2), osteoarthritis (1), and inflammatory arthritis, cause unknown (1), were followed for a mean of 6.8 years. Severe pain was the primary indication for surgery, and consistent and substantial pain relief was achieved. Most patients also had limited ambulatory and functional improvement. Computer analysis showed that this improvement was related only to preoperative walking and function and a combined hip and knee flexion of at least 190 degrees. All other parameters had no correlation with walking and function improvement. Of the 104 arthroplasties (52 hips and 52 knees), six implants (4 hips and 2 knees) in two patients failed and another seven implants (2 hips and 5 knees) in five patients were revised. Of the remaining 91 implants, 89 were clinically stable, and only two hip implants in two patients appeared destined for revision. However, when radiographic review was included, nine acetabular components, three THA femoral components, and five tibial components in 12 patients had some evidence of impending aseptic loosening, despite low patient activity levels.
In dogs, resection of a length of the ulna equal to twice the diameter of the mid-shaft leaves a defect which consistently fails to unite. In response to an implant of 100 mg of bovine bone morphogenetic protein (BMP), the defect becomes filled by callus consisting of fibrocartilage, cartilage and woven bone within four weeks. The cartilage is resorbed and replaced by new bone in four to eight weeks. Woven bone is then resorbed, colonised by bone marrow cells and remodelled into lamellar bone. Union of the defect is produced by 12 weeks. Control defects filled with autogeneic cortical bone chips unite after the same period. In regeneration induced by bone morphogenetic protein (BMP) and in repair enhanced by bone graft, union depends upon the proliferation of cells within and around the bone ends. Our working hypothesis is that BMP induces the differentiation of perivascular connective tissue cells into chondroblasts and osteoprogenitor cells and thereby augments the process of bone regeneration from the cells already present in the endosteum and periosteum.
An edited summary of an Interdepartmental Conference arranged by the Department of Medicine, UCLA School of Medicine, Los Angeles. William M. Pardridge, MD, Associate Professor of Medicine, is Director of Conferences.
Bone morphogenetic protein and bone-derived growth factors are biochemical tools for research on induced cell differentiation and local mechanisms controlling cell proliferation. Bone morphogenetic protein irreversibly induces differentiation of perivascular mesenchymal-type cells into osteoprogenitor cells. Bone-derived growth factors are secreted by and for osteoprogenitor cells and stimulate DNA synthesis. Bone generation and regeneration are attributable to the co-efficiency of bone morphogenetic protein and bone-derived growth factors.
Human bone morphogenetic protein (hBMP) was chemically extracted from demineralized gelatinized cortical bone matrix by means of a CaCl2 X urea inorganic-organic solvent mixture, differential precipitation in guanidine hydrochloride, and preparative gel electrophoresis. hBMP is isolated in quantities of 1 mg/kg of wet weight of fresh bone, and has the amino-acid composition of an acidic polypeptide. The mol wt is 17 to 18 k-Da (kilodaltons). Implants of the isolated 17-kDa protein are very rapidly adsorbed and produce a smaller volume of bone than protein fractions consisting of 24-, 17-, and 14-kDa proteins. Since the isolated 24- and 14-kDA components lack hBMP activity, the kinetics of the bone morphogenetic processes including the function of other proteins as carrier molecules, await investigation.
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We report two double-blind, placebo-controlled studies of the effects of disodium etidronate (EHDP) on the incidence and severity of heterotopic ossification following total hip arthroplasty or spinal cord injury. The large placebo groups in these studies allowed the estimation of the incidence of heterotopic ossification in these patient populations. Heterotopic ossification occurred in 65% of patients after hip replacement and in the majority of these within 15 weeks. Clinically significant ossification occurred in 19% of affected patients. The incidence of heterotopic calcification after spinal cord injury was less (35%) but followed a similar natural history. Treatment with EHDP reduced the incidence and severity of lesions both at the time of stopping EHDP and up to 9 months after treatment.
UNLABELLED: Specimens of twelve osteosarcomas, five chondrosarcomas, one giant-cell tumor, and five extraskeletal soft-tissue sarcomas were transplanted into male athymic nude (nu/nu) mice. Survival of the transplant was determined by the volume-doubling time and the sex chromatin of the tumor cells obtained from two female patients. By these criteria and the similarity of the histological composition of the original tumor and the transplant, survival occurred in four of twelve osteosarcomas and four of five chondrosarcomas. Without any local infiltration of lymphocytes or plasma cells, or other evidence of cell-mediated immunity, the surviving tumors regressed by the fourth week after the operation. Transformed osteoblasts and osteoprogenitor cells were replaced by fibrous connective tissue or fibrogenic tumor-tissue cells. Osteocytes degenerated and disappeared from the lacunae. The one giant-cell tumor transplant survived, growing very slowly, but by the end of the first week after transplantation whorls of mononucleated cells appeared in sites previously occupied by multinucleated cells. Transplants of leiomyosarcoma, liposarcoma, and synovioma (one tumor of each) degenerated. One of two fibrosarcomas survived transplantation. The most striking reaction of the mouse host bed was to encompass six of twelve osteosarcomas and four of five chondrosarcomas in deposits of normal living cartilage, bone, and bone marrow. The incidence of new bone inducedy by living transplants was only slightly greater than by implants of freeze-dried killed osteosarcoma tissue. Not one of five extraskeletal sarcomas, living or dead, induced bone formation. These observations suggest that an osteoinductive agent is transmitted by some osteosarcomas and chondrosarcomas. This agent initiates differentiation of host mesenchymal cells into normal non-tumorous cartilage and bone, which later colonized by bone marrow. CLINICAL RELEVANCE: Our observations present experimental evidence of the origin of the envelope of normal non-tumorous bone that may surround tumorous bone. In 1926, Phemister recognized the clinical significane of this envelope as a pitfall in the differential diagnosis of malignant bone tumors, chondrosarcoma, myositis ossificans circumscripta, and other neoplasms. He emphasized the importance of examining the entire specimen for the distribution of deposits of tumorous and normal bone. The induction of normal bone formation in the host bed surrounding transplants of osteosarcomas and some chondrosarcomas (but not transplants of fibrosarcoma, liposarcoma, or leiomyosarcoma) is evidence of a specific tumor-cell characteristic. Thus, the bone inductive response is not an unspecific reaction to injury from expansion or of tumor growth but a biological response to tumor-cell products. Transplants of human malignant tumors growing in the thymus-deficient mouse can be treated by combinations of radiation, amputation, and new chemotherapeutic agents...
An osteoid osteoma, excised from the neck of the femur of a 23-year-old man, was cut into four 1.5 mm3 fragments and immediately transplanted into muscle pouches in athymic nude mice. One fragment was devitalized by lyophilization before implantation. The viable tumor cell xenografts grew, differentiated into uncalcified osteoid, and retained the characteristics of the original tumor. The killed implants were resorbed, but both the surviving viable and nonviable tumor tissue induced the connective tissue cells of the mouse host bed to proliferate and differentiate into normal cartilage and calcified bone. The mouse new bone deposits were remodeled and colonized by bone marrow, a tissue not seen in osteoid osteomas. These observations suggest that the sclerotic bone shell characteristic of osteoid osteomas may be an inductive reaction of host bed tissue to an osteoma cell product that is comparable to bone morphogenetic protein (BMP) produced by normal bone cells and transferred by normal bone matrix.
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Histophysiology, ultrastructure, chemical analyses of transplants and implants of Dunn and Ridgway mouse osteosarcomas demonstrate that tumorigenesis is a manifestation of deranged morphogenesis in developing mesenchymal cell populations. The end product of development is defective, incompletely calcified, disorganized bone without any inclusions of bone marrow tissue. When Dunn osteosarcoma is freeze-dried and then implanted, the tumor is resorbed and replaced by deposits of normal cartilage, bone, and bone marrow. Freeze-dried Ridgway osteosarcoma is replaced only by a fibrous connective tissue scar. Disaggregated Dunn tumor osteoblasts synthesize a trypsin-labile collagenase-resistant cell surface localized bone morphogen. Tumor matrix stroma, prepared by sequential chemical extraction of soluble non-collagenous proteins also contains significant quantities of the same bone morphogen. Tumor tissue pulverized to particle size as small as 44 micrometer3 transmitted bone morphogen more rapidly than intact tumor tissue. The total tumor cell and stroma mediated bone morphogen produces three times more normal bone than normal cortical bone matrix. Our working hypothesis is that a normal bone morphogenetic polypeptide (BMP) is synthesized by Dunn osteosarcoma cells and retained by the tumor matrix stroma. Neither the mechanism of transmission nor the mesenchymal cell receptor sites of BMP are known.