The inorganic part of hard tissues (bones and teeth) of mammals consists of calcium phosphate, mainly of apatitic structure. Similarly, most undesired calcifications (i.e. those appearing as a result of various diseases) of mammals also contain calcium phosphate. For example, atherosclerosis results in blood-vessel blockage caused by a solid composite of cholesterol with calcium phosphate. Dental caries result in a replacement of less soluble and hard apatite by more soluble and softer calcium hydrogenphosphates. Osteoporosis is a demineralization of bone. Therefore, from a chemical point of view, processes of normal (bone and teeth formation and growth) and pathological (atherosclerosis and dental calculus) calcifications are just an in vivo crystallization of calcium phosphate. Similarly, dental caries and osteoporosis can be considered to be in vivo dissolution of calcium phosphates. On the other hand, because of the chemical similarity with biological calcified tissues, all calcium phosphates are remarkably biocompatible. This property is widely used in medicine for biomaterials that are either entirely made of or coated with calcium phosphate. For example, self-setting bone cements made of calcium phosphates are helpful in bone repair and titanium substitutes covered with a surface layer of calcium phosphates are used for hip-joint endoprostheses and tooth substitutes, to facilitate the growth of bone and thereby raise the mechanical stability. Calcium phosphates have a great biological and medical significance and in this review we give an overview of the current knowledge in this subject.

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Biological and medical significance of calcium phosphates.

The current focus of medicine on molecular genetics ignores the physical basis of disease even though many of the problems that lead to pain and morbidity, and bring patients to the doctor's office, result from changes in tissue structure or mechanics. The main goal of this article is therefore to help integrate mechanics into our understanding of the molecular basis of disease. This article first reviews the key roles that physical forces, extracellular matrix and cell structure play in the control of normal development, as well as in the maintenance of tissue form and function. Recent insights into cellular mechanotransduction--the molecular mechanism by which cells sense and respond to mechanical stress--also are described. Re-evaluation of human pathophysiology in this context reveals that a wide range of diseases included within virtually all fields of medicine and surgery share a common feature: their etiology or clinical presentation results from abnormal mechanotransduction. This process may be altered by changes in cell mechanics, variations in extracellular matrix structure, or by deregulation of the molecular mechanisms by which cells sense mechanical signals and convert them into a chemical or electrical response. Molecules that mediate mechanotransduction, including extracellular matrix molecules, transmembrane integrin receptors, cytoskeletal structures and associated signal transduction components, may therefore represent targets for therapeutic intervention in a variety of diseases. Insights into the mechanical basis of tissue regulation also may lead to development of improved medical devices, engineered tissues, and biologically-inspired materials for tissue repair and reconstruction.

Mechanobiology and diseases of mechanotransduction

Biphasic calcium phosphate (BCP) bioceramics belong to a group of bone substitute biomaterials that consist of an intimate mixture of hydroxyapatite (HA), Ca(10)(PO(4))(6)(OH)(2), and beta-tricalcium phosphate (beta-TCP), Ca(3)(PO(4))(2), of varying HA/beta-TCP ratios. BCP is obtained when a synthetic or biologic calcium-deficient apatite is sintered at temperatures at and above 700 degrees C. Calcium deficiency depends on the method of preparation (precipitation, hydrolysis or mechanical mixture) including reaction pH and temperature. The HA/beta-TCP ratio is determined by the calcium deficiency of the unsintered apatite (the higher the deficiency, the lower the ratio) and the sintering temperature. Properties of BCP bioceramics relating to their medical applications include: macroporosity, microporosity, compressive strength, bioreactivity (associated with formation of carbonate hydroxyapatite on ceramic surfaces in vitro and in vivo), dissolution, and osteoconductivity. Due to the preferential dissolution of the beta-TCP component, the bioreactivity is inversely proportional to the HA/beta-TCP ratio. Hence, the bioreactivity of BCP bioceramics can be controlled by manipulating the composition (HA/beta-TCP ratio) and/or the crystallinity of the BCP. Currently, BCP bioceramics is recommended for use as an alternative or additive to autogeneous bone for orthopedic and dental applications. It is available in the form of particulates, blocks, customized designs for specific applications and as an injectible biomaterial in a polymer carrier. BCP ceramic can be used also as grit-blasting abrasive for grit-blasting to modify implant substrate surfaces. Exploratory studies demonstrate the potential uses of BCP ceramic as scaffold for tissue engineering, drug delivery system and carrier of growth factors.

Biphasic calcium phosphate bioceramics: preparation, properties and applications.

This invention provides a fibrin sealant bandage or dressing, wherein said fibrin sealant may be supplemented with at least one composition selected from, for example, one or more regulatory compounds, antibody, antimicrobial compositions, analgesics, anticoagulants, antiproliferatives, anti-inflammatory compounds, cytokines, cytotoxins, drugs, growth factors, interferons, hormones, lipids, demineralized bone or bone morphogenetic proteins, cartilage inducing factors, oligonucleotides, polymers, polysaccharides, polypeptides, protease inhibitors, vasoconstrictors or vasodilators, vitamins, minerals, stabilizers and the like. Also disclosed are methods of preparing and/or using the unsupplemented or supplemented fibrin sealant bandage or dressing.

Supplemented and unsupplemented tissue sealants, methods of their production and use

Although epidemiological and biochemical evidence suggests that aluminium may be associated with Alzheimer's disease (AD), there is no convincing proof of a causal link for aluminium in disease progression. We have completed a two year, single-blind study to investigate whether the progression of dementia could be slowed by the trivalent ion chelator, desferrioxamine. 48 patients with probable AD were randomly assigned to receive desferrioxamine (125 mg intramuscularly twice daily, 5 days per week, for 24 months), oral placebo (lecithin), or no treatment. No significant differences in baseline measures of intelligence, memory, or speech ability existed between groups. Activities of daily living were assessed and videorecorded at 6, 12, 18, and 24 month intervals. There were no differences in the rate of deterioration of patients receiving either placebo or no treatment. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills as assessed by both group means (p = 0.03) and variances (p less than 0.04). The mean rate of decline was twice as rapid for the no-treatment group. Appetite (n = 4) and weight (n = 1) loss were the only reported side-effects. We conclude that sustained administration of desferrioxamine may slow the clinical progression of the dementia associated with AD.

Intramuscular desferrioxamine in patients with Alzheimer's disease

CONCLUSIONS: Hearing may be conserved in adults after implantation with the Nucleus Contour Advance perimodiolar electrode array. The degree of hearing preservation and the maximum insertion depth of the electrode array can vary considerably despite a defined surgical protocol. Residual hearing combined with electrical stimulation in the same ear can provide additional benefits even for conventional candidates for cochlear implantation. OBJECTIVES: We present preliminary results from a prospective multicentre study investigating the conservation of residual hearing after implantation with a standard-length Nucleus Contour Advance perimodiolar electrode array and the benefits of combined electrical and acoustic stimulation. MATERIAL AND METHODS: The subjects were 12 adult candidates for cochlear implantation recruited according to national selection criteria. A "soft" surgery protocol was defined, as follows: 1-1.2-mm cochleostomy hole anterior and inferior to the round window; Nucleus Contour Advance electrode array inserted using the "Advance-off-stylet" technique; and insertion depth controlled by means of three square marker ribs left outside the cochleostomy hole. These procedures had been shown to reduce insertion forces in temporal bone preparations. Variations in surgical techniques were monitored using a questionnaire. Pure-tone thresholds were measured pre- and postoperatively. Patients who still retained thresholds <90 dB HL for frequencies up to 500 Hz were re-fitted with an in-the-ear (ITE) hearing aid. Word recognition was tested in quiet and sentence perception in noise for the cochlear implant alone and in combination with an ipsilateral hearing aid. RESULTS: Hearing threshold level data were available for 12 patients recruited from 6 of the centres. Median increases in hearing threshold levels were 23, 27 and 33 dB for the frequencies 125, 250 and 500 Hz, respectively. These median increases include the data for two patients who had total loss of residual hearing due to difficulties encountered during surgery. "Cochlear view" X-ray images indicated that the depth of insertion varied between 300 and 430 degrees, despite modest variations in the length of the electrode inserted (17-19 mm). The insertion angle had some influence on the preservation of residual hearing at frequencies of 250-500 Hz. Six of the 12 patients retained sufficient hearing for effective use of an ipsilateral ITE hearing aid (< or = 80 dB HL at 125 and 250 Hz; < or = 90 dB HL at 500 Hz). Word recognition scores in quiet were improved from 10% to 30% with the cochlear implant plus ipsilateral hearing aid in 3 patients who had at least 3 months postoperative experience. Signal:noise ratio thresholds for sentence recognition were improved by up to 3 dB. Patients reported that they experienced greatly improved sound quality and preferred to use the two devices together.

Preservation of residual hearing with cochlear implantation: how and why.

OBJECTIVE: To analyze predictive factors of outcome after ossiculoplasty using a standard ossicular prosthesis system. STUDY DESIGN: Retrospective review of 140 ossiculoplasties, performed by the same senior surgeon, with titanium prostheses. SETTINGS: Academic hospital and tertiary referral center. PATIENTS: All patients undergoing ossiculoplasty with Spiggle and Theis or Kurz titanium total and partial prostheses. Documented, postoperative follow-up had to be provided. A total of 129 patients (140 ears; 53 men and 76 women) were evaluated. INTERVENTIONS: These included ossiculoplasties using 75 Spiggle and Theis prostheses (30 partial and 45 total) and 65 Kurz prostheses (35 partial and 30 total). MAIN OUTCOME MEASURES: Mean preoperative and postoperative air-bone gaps and the changes in mean hearing loss were analyzed using a four-frequency (500, 1,000, 2,000, and 3,000 Hz) pure tone average. Success rate was defined as postoperative air-bone gap within 20 dB. A one-way analysis of variance was used to analyze group differences. A multivariate statistical analysis was then undertaken to define the significant factors. RESULTS: There were no statistical difference between the Spiggle and Theis and the Kurz prostheses. Multivariate statistical analysis has identified the predictive value of the presence or absence of the malleus handle and the mucosal status of the middle ear in the prognosis of ossiculoplasties. CONCLUSION: Anatomical and technical factors diversely affect the functional outcome of tympano-ossiculoplasties. A better knowledge of their predictive value will enable accurate, preoperative, individual assessment when counseling patients with regard to the success of any proposed intervention. The use of these factors will also permit precise matching of future series to allow accurate comparisons.

Prognostic factors in ossiculoplasty.

This report presents the long-term results 3 years after primary myringoplasties performed with formolized fascia temporalis autografts. The overall closure rate was 87.7% of cases, with improvement in hearing in 67.2% of cases. The best results were achieved with total perforations, and not with partial posterior perforations, contrary to popular opinion. The anterior perforations were the most difficult to close. Anterior angle blunting was avoided by careful technique. Although the results of myringoplasty are clearly better in adults than in children, there is not a determined "frontier age" before which a child may not undergo operation. The state of the middle ear at the time of operation influences surgical outcome: wet ears have a higher rate of perforation, myringitis, and retraction pocket. Medical treatment is recommended prior to surgery in every discharging ear, as a diagnostic method rather than a therapeutic one. If the ear remains wet, chronic otitis media should be considered rather than simple perforation of the eardrum, and a mastoidectomy should be combined with the myringoplasty.

Myringoplasty: long-term results in adults and children.

Following our previous experimental studies on the performance of macroporous biphasic calcium phosphate (MBCP) in canine mastoid cavities, we used this material in patients requiring surgical intervention. Twenty-two cases were selected, and in eight specific cases a biopsy specimen was taken. Histologic, ultrastructural, and microanalysis studies were performed. This study demonstrates the effectiveness of MBCP implants as bone graft substitutes for mastoid cavity obliteration. Clinical evaluation of the series and histologic and ultrastructural results demonstrated the bioactivity and osteoconduction of this material, with partial transformation of MBCP granules into lamellar bone after several months.

Macroporous biphasic calcium phosphate efficiency in mastoid cavity obliteration: experimental and clinical findings.

Immunological mechanisms are thought to play an important role in the pathogenesis of some cochleo-vestibular diseases. This study attempts to present further evidence of autoantibodies reactive against guinea pig inner ear proteins found in patients with autoimmune inner ear diseases (AIED) and specifically identifies the main target antigens of these antibodies. Sera from 110 patients with a clinical diagnosis of either rapidly progressive sensorineural hearing loss (n = 32). Meniere's disease (n = 41), sudden deafness (n = 6) or other aetiologies of hearing loss (n = 11) were screened by the Western blot technique. Forty-four percent of the patients' sera had antibodies to several inner ear proteins, of which the 30, 42 and 68 kDa proteins were found to be the most reactive. These highly reactive proteins were identified by gas-phase micro sequencing after digestion with trypsin and separation of peptide fragments by high-performance liquid chromatography. A partial sequence of each protein was determined. These data, together with those obtained from 2-dimensional gel electrophoresis followed by Western blotting, demonstrated that the 30 and 42 kDa inner ear proteins are the major peripheral myelin protein P0 and the beta-actin protein, respectively, while sequence analysis indicated that the 68 kDa protein is novel. These findings further support the hypothesis that several populations of antibodies may contribute to the enhanced immunological activity of AIED patients. They also add a new dimension to our knowledge of AIED and may open new avenues in the development of simple serological assays, which are easier to perform and more rapid than Western blotting.

Michel Gersdorff

Papers

Preservation of residual hearing with cochlear implantation: how and why.

Prognostic factors in ossiculoplasty.

Myringoplasty: long-term results in adults and children.

Macroporous biphasic calcium phosphate efficiency in mastoid cavity obliteration: experimental and clinical findings.

Inner Ear Autoantibodies and their Targets in Patients with Autoimmune Inner Ear Diseases