Antipyrine disposition and metabolism in conscious, unrestrained Sprague-Dawley rats after 25% or 50% Fluosol hemodilution is reported. 25% hemodilution depressed antipyrine metabolism for 24 hours by primarily inhibiting cytochrome P-450. However, 50% hemodilution produced significant increases in the cytochrome P-450 activity after 48 hours. 25% hemodilution significantly reduced the antipyrine Vd at 0.5 and 72 hours. After 50% hemodilution, the Vd alternated between values greater and less than control throughout the 72hour study.

For any viable blood substitute, questions of long-term storage and shelf-life must be addressed. Recently, we have made great progress in improving the stability of the blood substitute, liposome encapsulated hemoglobin (LEH). We have concentrated our efforts on protecting LEH in solution and in the long-term preservation of LEH by lyophilization. In particular, we have been able to retard and in some cases, reverse the oxidative process of metHb formation in solution by the addition of antioxidants such as NADH and glutathione. We have been able to regenerate Hb preparations with 60% metHb by the addition of 10 mM NADH and glutathione. In these preparations addition of these antioxidants results in a decrease of metHb levels from 62% to 15% over the course of 12.5 days at 4°C. We have also explored the use of protective solutes such as the disaccharide trehalose in the preservation of LEH in the freeze-dried state. Addition of increasing amounts of trehalose and other disaccharides results in the inhibition of lyophilization-induced fusion events and in the retention of hemoglobin within the unilamellar liposomal vesicles following rehydration.

Near total blood replacement in rats has been accomplished with perfluorochemical (PFC) preparations containing hydroxyethylstarch and electrolytes. F-dimethyladamantane (F-DMA) was used alone or mixed with F-N,N-dimethylcyclohexylmethylamine (F-CHA). These compounds were emulsified to yield particles approximately 150 to 250 nanometers in diameter. The nonionic surfactant, Pluronic F68, was used as the emulsifying agent. Over ninety percent of the rats survived when their hematocrits were taken to 3 volume percent or lower from a pre-perfusion value of about 44 volume percent. In spite of the reduction in total mixed venous oxygen concentration, the oxygen partial pressure rose. During the perfusion the rats breathed 100 percent oxygen, but during the subsequent period this was decreased 10 percent per day. Six to 7 days later the hematocrits had risen to 30 to 40 volume percent. Thereafter the animals continued to develop and grow.

The passage of the Medical Device Amendements to the Food Drug and Cosmetic Act on May 28, 1976 placed a huge number of products under the regulatory authority of the Food and Drug Administration (FDA). This increased responsibility took many forms related to device evaluation which will be discussed in this paper. In order to institute control of all devices it was necessary to “take inventory” of what was on the market. This was accomplished by establishing device panels for the various medical specialties composed of experts familiar with the devices areas who compiled a generic device list for their specialty areas. Each device was classified according to its hazard potential and existing data related to safety and effectiveness.

Premarket review processes as prescribed by the Medical Device Amendments of 1976 to the Food, Drug, and Cosmetic Act greatly affect the use of materials in medical products, especially for implantable devices. The premarket approval process can have a particularly important role in eventual commercial medical uses of materials. Managing the process properly is often critical to the success or failure of a product.

A review of the law and regulations as they pertain to premarket approval is presented. Subjects included in this overview are prediction of process time and costs, examination of potential pitfalls in the process, recommendations on organizing for successful completion of the process and handling the relationship with FDA.

Specific materials related issues that are likely to arise are noted.

Cooperation is one avenue being pursued among American industry, labor, and government to ensure a strong internationally competitive U.S. economy. At the National Bureau of Standards (NBS), we have a program which facilitates cooperative interaction. This article focusses on one of our longest running cooperative projects, dental materials research.

Methods have been devised for preparation of composite hydroxylapatite (HA)-plaster of Paris (PP) implants for augmentation of edentulous alveolar ridges. These implants may be used to correct bony defects, deficiencies, and related contour abnormalities. The HA-PP implants are customized to exactly conform to the underlying bony architecture. They can either be preformed and sterilized for later use or made directly or indirectly at surgery. In addition to maintaining the desirable biological, chemical and mechanical properties of HA, the HA-PP implant provides complete containment of the HA particles in the desired implant shape. The PP also contributes to an enhanced bony healing response and the HA-PP implant is very biocompatible.

The handling property and short term biological response to a new composite of fibrillar collagen (FC) and porous calcium phosphate (HA/TCP) were studied. A 4 mm by 20 mm defect was created in the femora of rabbits. The rabbits were divided into four treatment groups and sacrificed from each group at 4, 8 and 12 weeks. In each group, the defect was treated as follows: in Group I with autogenous bone marrow; in Group II with FC and HA/TCP; and in Group III with FC and HA/TCP with bone marrow in volume ratio of 3:1. In the fourth group, the defect was unfilled. The femora were excised and studied by microradiography or histology or both. The FC could improve the handling property of the HA/TCP granules. Although the composite of FC and HA/TCP was not osteoinductive, the defects in Groups II and III showed good healing at 12 weeks without signs of inflammation. The results showed the composite of FC and HA/TCP to be an effective filler for large bone defects especially when mixed with autogenous bone marrow.

Bony defects in the alveolar bone, maxilla, paranasal region, and the floor of the nose were corrected in 75 consecutive patients with a composite bone graft. The composite bone graft is a mixture of a slurry of corticocancellous cranial bone, hydroxyapatite (R), and Bacitracin powder, and thrombin. The paste-like composite is used to pack the defect and correct the deformity. Complete bony immobilization, done externally or internally, is necessary during the healing phase of the bone composite. The patients were longitudinally evaluated, and the healing of the bone was assessed radiographically and clinically. Two major complications occurred during the healing phase at the recipient sites: one may have been indirectly related to the donor site, and the second was related to the age of the patient and the previous surgeries contributed to the partial loss. Composite bone grafts produce better results due to faster solidification of the grafts which acts acts as a strong inductive matrix. The graft is used in the alveolar ridge and in hard tissue augmentation of the bony structures in the maxilla. The prospectus for the future is to see more composites grafting, since it combines the advantages of the materials used.

The biocompatibility, osteoconduction and biodegradation characteristics of calcium phosphate ceramics is controversial. Few comparative studies have controlled for material properties as well as biological influences. In this study, we compared the in-vivo response of implants made porous (500 μm pores) using the Replamineforu™ process and composed of hydroxyapatite (HA), sintered hydroxyapatite (SHA), tricalcium phosphate (TCP) or calcium carbonate (CC). In ten rabbits, rod-shaped implants (5mm d × 10m 1) of each material were randomly press-fit into two bilateral defects of either the bicortical iliac crest or unicortical proximal tibial metaphysis. Explants were harvested at 1 to 9 months, sectioned midsagitally with half embedded in plastic for qualitative histomorphometry, and the other half decalcified and stained for histology. The acute and chronic inflammatory response was minimal for all implants. The osteoconduction properties were similar for the calcium phosphate materials, resulting in repair of the cortical defects within three months with partial bony fill of the medullary canal. CC completely degraded by three months, causing incomplete defect closure in some cases. TCP partially degraded in the medullary canal, but remained when surrounded by bone in the cortex. HA and SHA did not degrade. In summary:

In the past, the effectiveness of intraosseous fixation devices in Hydroxyapatite (HA) implanted and bone grafted areas has not been well defined. Previous definitions of the histologic meaning of osteointegration have implied that only through contact with viable calcified osseous matrix or all implant surfaces is an intraosseous fixture fully integrated or attached (1). Such a definition would preclude the use of these implants in previously bone grafted, HA implanted, or otherwise compromised sites. The purpose of this work was to study the surface interface of metallic intraosseous fixtures in HA implanted and xenogeneic bone-implanted mandibular extraction sockets of mature Macaca fascicularis monkeys and Papio anubis baboons.

We have developed a particulate composite bone cement consisting of a particulate phase of tricalcium phosphate (TCP) particles bound together by a polymeric matric phase (PPF). This matrix hardens through a free radical polymerization reaction in vivo within several minutes after mixing. The initial mechanical strength of our particulate composite bone cement results from the matrix, but over time this degrades and the strength is augmented by bone ingrowth and incorporation of the tricalcium phosphate particles. Possible orthopaedic applications include fixation of fractures, augmenting fixation of implants in osteoporetic bone, and temporary stabilization of bone ingrowth prostheses.

Repair was compared in 4.4mm experimental rat mandibular ramus defects implanted with dense or porous HA particles with or without a plaster binder. Animals were sacrificed 6 months postimplantation. Specimens underwent gross, radiographic, histochemical and X-ray microanalytical examination. Gross and radiographic examinations showed good particle containment or retention only in defects filled with implants containing plaster. Only porous HA/plaster filled defects showed bone formation throughout the implant when examined histochemically by the PATS reaction and by X-ray microanalysis. They also showed greater radiographic opacity compared to dense HA/plaster implants. Only porous HA/plaster implants showed macroscopic bone formation. Examination of defects filled with porous HA/plaster or porous HA alone by the PATS reaction showed new cancellous bone around, and through the pores of, retained particles. The dense HA/plaster implants showed some new bone around the rims of the defects with only occasional bony incorporation of an HA particle. Dense particles in other areas showed only soft tissue encapsulation. Defects implanted with dense HA without plaster showed no new bone formation but retained particles were incorporated by fibrovascular tissue.

Composite hydroxylapatite (HA)/plaster alloplasts were studied for frontal and parietal cranioplasty. The experimental defects were created in 61 anesthetized cats. They were filled with a moist 2:1 mixture of durapatite/plaster or Interpore/plaster containing 0.85% potassium sulfate. After setting, the implant site was sutured. The filled defects were very firm by physical examination and showed little particle scatter by radiography. At the time this report was prepared only 43 of the cat skulls were available for examination. After sacrifice, postmortem visual examination (VE) of the skulls suggested that new bone had formed over some implants. In most implants, however, VE could not determine whether new bone had formed between the HA particles. Probing examination (PE) of the parietal implants with a periodontal explorer gave a better indication; the presence of new bone rather than soft tissue between the HA particles was confirmed by x-ray microanalysis. The ventral surfaces (VS) of the parietal implants showed greater degrees of bone formation by PE; only 12 of 43 parietal implants showed a high degree of bone formation on the dorsal surfaces (DS) by PE whereas 34 of 43 showed this on the VS. The highly significant difference (^3X) in the amount of bone formation on the VS compared with the DS suggests that this osteogenesis, like that observed in cranial trauma, may be stimulated by the dura which acts as a periosteum by supplying blood vessels to the implant.

Infrabony defects of 230 periodontal patients have been treated surgically by implantation. These lesions of alveolar bone, up to nineteen per patient, generally displayed pocket depths of at least 8mm and were associated with teeth showing pronounced mobility. Approximately 50% of these teeth could have ordinarily been condemned to extraction. In this study, scaling, root planing, and polishing were performed and patients were instructed in oral hygiene measures prior to surgical implantation. A 1:1 mixture of dense sintered hydroxylapatite(HA) particles (OrthoMatrix HA-500) with plaster of Paris (USG Medical Grade Calcium Sulfate Hemihydrate B, containing 0.85% K2SO4) was moistened with a minimum amount of saline. The mixture was then implanted into the dried defect. After setting, the operative site was closed with silk sutures. The plaster bound the HA particles in the defects and prevented particle straying which frequently occurs when they are implanted with saline alone or with other vehicles. There was an almost immediate and sustained diminution in tooth mobility at most implantation sites. Good retention of particles was seen on physical and radiographic examination of most defects for the length of the study (5 years). Overall, there was a marked reduction in pocket depth and improvement in tissue tone and texture. Less than 1% of the teeth at the implantation sites have been lost. No significant inflammation has been observed. Increased radiopacity and resistance to probing suggest bone formation in some implanted defects. Implantation of periodontal osseous defects with the biocompatible HA/plaster composite appears to result in the clinical cessation of progressive periodontal disease.

Hydroxylapatite (HA) has been shown to be an efficacious bio-implant material in a number of surgical procedures[l]. A problem in the use of this material is that of particle migration away from the implant site. One method to resolve this problem is to mix the HA with calcium sulfate hemihydrate, CaSO4·0.5H2O, and allow the material to set to a gypsum/HA composite monolith[2]. The gypsum is resorbed by the body over a period of weeks, leaving the hydroxylapatite surrounded by newly generated tissue.

Composite hydroxylapatite/plaster of Paris implants, preformed or formed during the surgical implantation procedure, are undergoing study for the surgical reconstruction of craniofacial bones. It is frequently necessary to accelerate setting times of the hydroxylapatite/plaster (HA/PP) mixtures by the addition of potassium sulfate; in many of these cases rapid delivery of the moistened implant mixture to the surgical site may be achieved by employing a non-tapered syringe with a plunger. This device can facilitate implantation of quick-setting moistened mixtures through soft tissue tunnels or small incisions, and can result in a less invasive surgical procedure. During experimental surgery it was found beneficial to effect maximum compression of the moistened HA/PP mixture against a sterile glass plate prior to its extrusion from the cylinder. This resulted in elimination of excess water from the mixture. Discs formed from compressed mixtures showed greater mechanical or breaking strengths after setting than discs formed without prior compression when evaluated with a Stokes Hardness-Tester. Examination by light and scanning electron microscopy confirmed the greater compactness of the compressed mixtures.

One important, and perhaps the crucial reason for lack of success in permanent implants is their colonization by bacteria (ref. 1,2 ). There are various reports of bacteria lodging the surface implants and their success in escaping from the host's defense mechanisms. Quantitative studies of ecosystems have established that more than 99,9% of the bacteria within the system live in microcolonies within biofilms that are adherent to inert surfaces ( ref. 3,4 ). Many of the bacteria that colonize the surfaces of clinical biomaterials also grow in thick, adherent biofilms ( 10, 11 ). - They may be introduced when a biomaterial is implanted or they may be carried to the surface of the biomaterial by a transient bacteriemia. Once there, their adherence is probably a virulence factor and it may enhance their protection against both antibiotics and natural host defences. The adherence of bacteria in industrial systems protect them from chemical and biocides and antiseptics. Adherence of autochtonous bacteria to ephitelium protects them from surfactants, opsonizing antibodies and phagocytic macrophages ( 12,13,14,15,16,17 ). - Apparently what is needed is antibacterial protection confined to the surface of the implant to prevent bacterial invasion of the implant. Antimicrobial penetration into the surrounding tissues is probably unnecessary.

The tissue compatibility of the hydroxylapatite silver phosphate ceramics could be demonstrated in the cortex of mongrel dogs. The assessment was done by histomorphometrical methods. The toxicity depends on the content of silver phosphate and the method of manufacture.- In treatment of an experimentally induced osteomyelitis in dogs, hydroxylapatite silver phosphate containing granules had better success than an autologous spongiosa graft or hydroxylapatite granules without the agent.

Analysis of pre- and postoperative casts is essential in evaluating the efficacy of hydroxylapatite implant procedures for denture support. Computergraphics have been used to quantitate the changes in anatomic contour of occlusal surfaces of teeth and in the diagnosis and treatment of patients with craniofacial malformations. They may prove to be a useful adjunct in the planning and execution of preprosthetic oral and maxillofacial surgery for ridge augmentation. Thus computergraphics may be useful in surveying pre- and postaugmentation casts and evaluating clinical outcomes. In addition, computergraphics may also be useful in evaluating the utility of various surgical techniques used to augment ridges. In this study, pre- and postsurgical maxillary and mandibular casts were made from tissue displacing, irreversible hydrocolloid impressions. A comparison of pre- and postsurgical ridge contours, surface areas and volumes were derived from computer digitized two-dimensional tracing of casts sectioned in the frontal plane. This was accomplished using a three-dimensional computergraphics program that reconstructed digitized two-dimensional images into a three-dimensional image which displayed ridge contours, surface areas and volumes. The application of computergraphic technology may also prove useful in quantitating and mapping time-dependent morphological changes in ridges supporting the prostheses. Thus this technique may be useful in monitoring resorption patterns in underlying bone as well as in the revision and compaction of implanted materials.