HMPA Copolymer Imaging Agent for Radiological Imaging Orthopedic Implant LooseningAssessment and Valuation[Type the abstract of the document here. The abstract is typically a short summary of the contents of the document. Type the abstract of the document here. The abstract is typically a short summary of the contents of the document.]

2009

Amanda FrasherCarroll Bo Allen

9/9/2009

HMPA Copolymer Imaging Agent for Radiological Imaging Orthopedic Implant Loosening: Assessment and Valuation

The New Invention Notice below has been duly filed and the subject of a license from UNeMed to Versalion Pharmaceuticals, LLC.

Currently, there is no effective modality for early screening and the subsequent therapeutic intervention of osteolysis of orthopedic or dental implants. The invention of a -(2-Hydroxypropyl) methacrylamide and Polyethylene Glycol copolymer Technology (HPMA-PEG) imaging agent for radiological imaging orthopedic implant loosening has the potential to fulfill these unmet needs. These screening agents will give enable early detection of orthopedic or dental implant loosening using routine medical imaging modalities such as MRI, SPECT or PET, the administered imaging agent will specifically report the active and potential osteolysis lesions associated with implant loosening. Concurrently, administration of UNEMED’s HPMA Copolymer –Dexamethasone (P-Dex) conjugate has unique properties that make it a strong candidate for the treatment of this pH sensitive dexamethasone containing copolymer conjugate which offers a simple solution to target a novel joint –specific directed therapy for these lesions and mitigate or heal the disease progression.

Versalion Consultant and the Radiology Clinical Program Coordinator at Northeast Iowa Community College, Amanda Frasher, observed this is great opportunity because of the increased orthopedic implants in patients. Based on her extensive experience in, “there is definitely an increase in the younger generation implants; also many physicians delay orthopedic implants when the patient is young because of the chance of osteolysis. This diagnostic/ preventive tool will allow them to give the patient what they need sooner. This would also potentially save in physical therapy, injections; doctor visits cost for patients that in limbo of attempting to delay surgery because of one the potential osteolysis. If this Diagnostic/preventive tool works, there would be a dramatic decrease in repeat implants for patients. This product can become a routine follow-up for all implant patients. It is a diagnostic tool and form of

preventive medicine. The potential savings for patient and insurance companies to prevent and/or start early treatments to mitigate osteolysis”.

Recent research has uncovered the possibility that osteolysis may involve more than the resorption or dissolution of bone tissue. According to Rocky S. Tuan, PhD, chief of the cartilage biology and orthopedics branch of the National Institutes of Arthritis and Musculoskeletal and Skin Diseases, recent data suggest that biologic effects on bone-forming cells—osteoblasts, osteoprogenitors, and adult mesenchymal stem cells (MSCs)—may also contribute to osteolysis. Research findings suggest the following mechanisms of particle bioreactivity that may contribute to osteolysis: exacerbated inflammation caused by elevated reactive oxygen species production by activated macrophages and osteoclasts; impaired periprosthetic bone formation secondary to disrupted osteogenesis; and compromised bone regeneration resulting from increased cytotoxic response and suppressed osteopenic differentiation of mesenchymal osteoprogenitors cells. This new concept opens up possibilities for the development of therapeutic agents that enhance bone formation. These agents would add to existing therapies—such as bisphosphonates—that inhibit bone destruction.

Total joint replacement (also known as total joint arthroplasty) is regarded among the most valued developments in the history of orthopedics. The procedure provides the surgeon the ability to relieve pain and restore function to patients whose joints have been destroyed by trauma or disease. Before 1983, most hip replacements in the United States were done using acrylic-based cements (e.g., polymethylmethacrylate) to attach the prosthetic components to the respective portions of the femur and pelvis of the patient. The area between the metal implant and the surrounding bone tissue was filled with acrylic cement. At that time, deterioration of the cement in some cases resulted in prosthetic loosening and recurrence of pain. In many cases, a revision operation, particularly with young and active patients was required. Unfortunately, when the revision operation was performed using acrylic cement, the success rate for the revision surgery was significantly lower than with the initial surgery.

In response to this problem, the prosthetic implant industry began to explore the feasibility of using porous-coated prosthetic implants, especially for use with active patients. The porous-coated method involves the use of implants with sintered metal porous surfaces. By way of a non-limiting example, beaded, sintered cobalt-chrome coatings may be used on a cobalt-chrome substrate, beaded, vacuum-sintered titanium coated may be used on a titanium substrate, or vacuum-sintered titanium fiber mesh pads may be used on a titanium substrate. Additionally, truss-like structures may be used on the substrate,. Typically, these porous coatings would be disposed on the surfaces of the prosthetic components in direct contact with the patient's bone tissue. For example, the stem portion of the femoral component and the outer surface of the acetabular component would be provided with these porous coatings.

Because cement is not required, these types of implants are sometimes referred to as either uncemented or cement less. As previously noted, the major difference between the porous-coated implants and the cemented implants is the metal surface of the porous-coated implants. Cemented implants typically have a smooth surface and the porous-coated implants have a rough surface resembling metal sandpaper. The porous surface allows surrounding bone tissue to grow into the pores of the porous coating; this essentially results in making the implant a part of the patient's body. The close contact to the bone tissue aids in holding the porous surfaced implant in position until bone ingrowth has occurred.

Unfortunately, all mechanical devices, including prosthetic implants, have a tendency to generate wear particles (e.g., debris), such as, particles of plastic or metallic material from the prosthetic components. In porous implants, the wear particles can migrate down into the pores of the porous coating. This may occur during loading (e.g., walking, jumping, running, and so forth) wherein the axial motion may cause "pistoning" of the implant. The pores may soon contain these wear particles after the implant has been installed, thus hindering new bone tissue growth into the pores of the porous implant. As a result, a condition known as osteolysis may occur. Osteolysis is generally defined as a type of particulate induced bone resorption, wherein the immune response of the patient causes the surrounding bone tissue around the implant site to resorb away from the prosthetic component. Osteolysis can and infrequently will lead to an aseptic loosening of the particular implant, and eventually, a subsequent implant failure. Therefore, a

porous implant exists and method for making the implant can induce osteolysis. The porous implant coating is now capable of preventing the infiltration of wear particles into the pores, but is simultaneously capable of permitting the ingrowth of new bone tissue into the pores. The treatment of osteolysis remains a clinical challenge.

As American, as well as global, populations age, life spans extend, and a demand of younger total joint replacement increases the revision surgeries associated with prosthetic wear are becoming common. In the year 2008, 43,000 revision hip replacements and 35,000 revision knee replacements were carried out in the USA. The majority revisions were due to wear-associated loosening and periprosthetic osteolysis. Revision procedures are technically more difficult than primary procedures due to the higher complication rate, a less predictable clinical outcome, and increased cost to patient. The significant bone loss that accompanies wear-related failure necessitates extensive bone grafting with special prosthetic devices. Each year 30,000 Americans undergo surgery to revise loosened orthopedic implants. In fact, periprosthetic osteosteolysis is the major complication following total joint replacement. As replacement of weight-bearing joints has yielded dramatic clinical results, loosening of these prostheses represents the major long-term complication effecting approximately 1% of patients each year. As more than one million orthopedic prostheses are implanted annually worldwide, this problem promises to escalate. Orthopedic implant loosening reflects generation of wear particles from articulating prosthetic joint surfaces and supporting cement, the latter consisting of polymethylmethacrylate (PMMA). Particles generated incite a chronic inflammatory response eventuating in osteoclastic bone resorption and mechanical failure of the implant. The molecular mechanisms underlying this clinically important event, referred to as “wear debris-induced osteolysis,” are enigmatic.

The osteolytic process attending prosthetic loosening is associated with formation, at the implant-bone interface, of a cellular “membrane” containing abundant tissue macrophages, many of which have ingested implant derived wear particles such as PMMA. Several macrophage-produced osteoclastogenic cytokines, including interleukins-1 and -6, 10–12, and tumor necrosis factor-a (TNF) are present in the tissue surrounding failed implants, and thus serve as potential mediators of wear particle-induced osteolysis. Hence, the most likely scenario holds that implant wear particles promote an inflammatory reaction consisting largely of fibroblasts and activated macrophages. Secretory molecules of the activated cells recruit osteoclasts, which are ultimately responsible for periprosthetic bone degradation. Thus, identification of pro-inflammatory cytokine(s) mediating the osteoclastogenesis of implant osteolysis is central to prevention of this complication.

Ultimately, osteoclasts appear at the membrane-bone interface prompting focal resorption. As cytokines, such as interleukin-1, interleukin-6, and TNF, which are abundant in periprosthetic tissues, enhance resorptive activity; it is likely that one or more of these soluble agents modulate the osteoclastogenesis attending orthopedic implant loosening. Hypothetically, there appears to be a soluble mediator of periprosthetic osteolysis that implant particles induce in bone marrow macrophages (BMMs), a protein specifically expressed when these cells commit to the osteoclast phenotype. The fact that tumor necrosis factor-a (TNF) is a potent osteoclastogenic agent while at the same time is the only soluble moiety known to be inductive, suggests that this cytokine may mediate implant particle induced osteoclastogenesis. Consistent with this hypothesis, prosthesis-derived wear particles, recovered at revision arthroplasty, dose-dependently prompt TNF secretion by BMMs. Similarly, particulate polymemthylmethacrylate, the major component of orthopedic implant cement, induces BMM expression of TNF mRNA and protein in a time- and dose-dependent manner. Perhaps the most successful implant procedure is total hip joint replacement surgery. Artificial total hip joint surgery has become an efficient and cost effective procedure in the treatment of patients with painful end-stage arthritis since the concept of low-friction artificial joint was established. The surgical outcome sought is pain relieve and restoration of the activity of walking in daily life. Globally, nearly 800,000 hip joints are replaced annually. In successful artificial total hip joint surgery, where the prosthesis remains adequately fixed over a period of years, the host response has a benign character and signs of immune inflammatory reaction are modest.

Total Hip Joint Replacement:

Reference the picture to the left and the following descriptions :

1. A total hip joint system consists of a cup and stem. In a cement type system, the cup and the stem are fixed to the acetabulum and the femur, respectively, with bone cement.

2. At the left is an X-ray picture of a Charney type

Ostensibly if the mechanical stress is properly transferred to the bone present around the implants, they can support joint function without loosening and causing periprosthetic osteolysis, thus assuring a longer and better prosthesis survival. However, loosening and osteolysis of implanted total hip joints occur even if the intervention and insertion of the prosthesis is technically well performed. A ten year survival rate of approximately 90% has been demonstrated for total hip joint surgery, and some of them have to be revised due to aseptic loosening and periprosthetic osteolysis.

Artificial total hip joints induce adaptive and reactive processes; they are reflected at the level of the tissue and the joint fluid phase. Debris from implants has been considered as a critical factor inducing a local host response. Host induction seems to be influenced by multiple factors including, but not limited to, the type of material and fixation, design of the implants, bone quality and health, as well the general health of the patient. The exact cause-effect has been the subject of three decades of debate and there is increasing concern about periprosthetic osteolysis and biocompatibility of total hip prosthesis. Ultra-high molecular weight polyethylene, ceramics, and metals are currently used as material for the gliding surface of artificial hip joints, in order to provide low friction. However, a gliding surface continuously produces wears, although modern technology provides better biocompatible implants to lessen the wear debris. Any type of debris is phagocytosed by monocytes/macrophages.

Wear and osteolysis following total joint arthroplasty occur as a result of a complex interaction of variables. These variables include patient-specific characteristics (e.g., weight, activity level) that affect the magnitude and direction of loads across the joint as well as joint kinematics; implant design and material factors that control how the implant components respond to the mechanical burden placed upon them. Equally important are surgical factors (e.g., component position, orientation) that can also affect joint loads and kinematics. When surgical technique is optimized, the ideal implant position is realized and the best possible wear performance of the total joint arthroplasty can be achieved. However, when malpositioned, damaged, or misassembled, a specific prosthesis may experience greatly increased wear. Osteolysis can occur as a response to periprosthetic particulate debris that results from and is dependent on material type as well as particle size, shape, and amount. The multiple factors influencing clinical wear performance of hip and knee arthroplasty can be separated into patient-specific, implant-specific, and surgical factors that contribute to wear directly or indirectly.

Patient-specific factors that affect joint loading or wear following hip and knee arthroplasty are listed in Table 1.

Table 1. Patient-specific Factors Affecting Joint Wear

Activity Level (activities of daily living, pivot-shift activities)

Body Mass Index and Body Weight

Gait mechanics (level and stairs)

Limb alignment

Implant time in situ

Preoperative diagnosis

Comorbidities

Special Cultural Demands (e.g., kneeling in Middle Eastern and Asian populations)

Revision versus Primary Surgery

Knee Anthropometrics (sex, Asian populations)

Total Hip Joint Replacement:

Reference the picture to the left and the following descriptions :

1. A total hip joint system consists of a cup and stem. In a cement type system, the cup and the stem are fixed to the acetabulum and the femur, respectively, with bone cement.

2. At the left is an X-ray picture of a Charney type

cup

stem

Race

Activity level gauged with pedometer measurements can vary as much as 45-fold between individuals following arthroplasty. Patients with active lifestyles often return to recreational activities that markedly increase joint-loading conditions (e.g., running, jumping, pivoting, stair climbing). Increased body weight can be associated with increased magnitude of force and altered kinematics, although the detrimental effects of excessive weight can be counterbalanced by decreased activity levels and loading cycles that accompany a sedentary lifestyle. In general, any patient-specific factors that increase the magnitude of joint load per step or the number of loading cycles per year will have an adverse effect on wear performance and can thus increase the rate and severity of associated osteolysis.

Selected preoperative diagnoses, such as post traumatic arthritis and osteonecrosis, have been associated with higher prosthesis failure rates when compared with osteoarthritis. These increased rates of aseptic loosening, wear, and osteolysis are most likely a consequence of the higher activity level and younger age of these patients. Due to the relatively high rates of knee osteoarthritis following many years of meniscal and anterior cruciate ligament injuries as a result to sports participation. These particular injuries lead to altered kinematics that can affect the onset and progression of arthritis (and hence the need for arthroplasty). The recent increase in young females with anterior cruciate ligament injuries resulting from sports participation will likely yield higher arthroplasty rates at younger ages in the cohort of female individuals currently aged 15 to 30 years, even when they are treated with surgical repair. This will increase the, already predominantly, female population of arthroplasty patients. Recent anthropometric data on differences between sexes and races indicate that patients who perform activities, such as deep flexion for kneeling, load implants beyond current design characteristics and risk increasing wear and associated osteolysis. The shifting demographics in the United States will lead to increased numbers of younger individuals undergoing arthroplasty. This shift, coupled with the expansion of indications for total joint arthroplasty to include more active patients, will result in increased risk of implant wear compared with the older, lighter, and less active arthroplasty populations of years past. Currently, many patients have higher expectations of hip and knee arthroplasty, exacerbated by media reports and direct-to-consumer marketing efforts by manufacturers, hospitals, and surgeons. Moreover, many patients are motivated to remain physically active after surgery, with some resuming participation in high-impact and competitive sports. This substantial shift in the type of patients seeking arthroplasty will have a potential adverse effect on wear performance.

Additionally, this makes comparison to historical data on wear performance in older, more sedentary arthroplasty patients and to earlier outcome studies difficult and may not provide accurate predictions for surgeons and their patients. In fact, surgeons are increasingly encountering patients seeking arthroplasty who are highly active and clinically symptomatic. These patients do not want to return to normal activity in a disabled state but expect to maintain their prior high activity level. This represents a major change in the

patient population undergoing total joint arthroplasty compared to prior decades. Coupled with demographic trends, this will result in a dramatic, nonlinear increase in the number of primary and revision arthroplasty procedures performed in the United States (Figures 1, 2 and 3).

Figure 1: This chart represents the age demographics of patients undergoing surgical total hip joint replacement in the Hospital of Special Surgery in New York, New York.

Figure 2:

This chart represents the changing age demographics of patients in the United States

Figure 3

These two charts represent the number of A, The projected number of primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) procedures in the United States from 2005 to 2030. B, The projected number of revision THA and TKA procedures in the United

States from 2005 to 2030. (Reproduced with permission from Kurtz S, Ong K, Lau E, Mowat F, Halpern M: Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 2007;89:780-785.)

Implant-specific factors that affect wear performance of both hip and knee arthroplasties are summarized in Table 2. In total hip arthroplasty, bearing options include metal or ceramic-on–compression-molded or highly cross-linked polyethylene, ceramic-on-ceramic, and metal-on-metal articulations. Improvements in wear resistance with all of these articulations compared with prior conventional ultra-high–molecular-weight polyethylene (UHMWPE) sterilized by gamma irradiation in air are supported at least by midterm (5-year follow-up) clinical data; long-term data currently are unavailable. Unlike total hip replacement, the primary choice of materials for the bearing surfaces in total knee arthroplasty has been limited to metal-on-polyethylene. Material issues have focused on the type of metal and surface characteristics, the type of UHMWPE, modularity (and associated backside wear), and the type of implant fixation. Studies have shown that wear and delamination are influenced by sterilization method, resin type, and manufacturing method.

Cross-linking has been shown to decrease wear in laboratory simulations, but alterations in mechanical properties in first-generation highly cross-linked polyethylene may adversely impact resistance to breakage, fatigue cracking, and the performance of locking mechanisms. This is especially true in poorly positioned implants and those experiencing excessive edge loading. Implant design may contribute to kinematic conditions that accelerate wear debris generation. Backside wear has been demonstrated in both modular metal-backed acetabular and tibial components. Several other design factors can influence wear of tibial knee components; these include modularity, UHMWPE insert thickness, locking mechanism, and presence of screw holes, inclusion of a mobile or rotating platform, and whether the posterior cruciate ligament is retained. All of these factors can influence contact stresses experienced by the UHMWPE insert and, thus, the wear of these components. Furthermore, a stable implant interface, regardless of type of fixation, can limit access of wear particles to the host bone, providing no gaps exist between the prosthesis and bone interface. Surgeon education, awareness, and selection of implants intraoperatively have a direct bearing on patient outcome.

Table 2 Implant-specific Factors Affecting Joint Wear

Implant Design Choices:Modularity versus monoblockRigid versus FlexibleLocking mechanism for modular componentsUHMWPE component thickness

Bearing couple conformityFixation (cemented versus ingrowht)Implant ConstraintImplant imping cement

Material:

Metallic alloy (Co-Cr-Mo alloy versus titanium alloy)Ceramic (alumina, zirconia, oxidized zirconium alloy)UHMWPE (highly cross-linked versus conventional)

Bearing Couple:

Metal-on- UHMWPECeramic-on-UHMWPEMetal-on-metalCeramic-on-Ceramic

Quality Control:

Lot-to-lot variabilityShelf life and packaging of UHMWPE componentsSterilization process (radiation versus ethylene oxide)Method of fixation

Surgical factors that affect the wear performance of hip and knee arthroplasty are listed in Table 3. Surgical factors have also been shown to play a role in wear mechanisms. Surgical technique affects the thicknesses of bone resection; implant sizing, alignment of each component, articulation and impingement with the opposing implant, and soft-tissue balance. All of these factors can influence the articulation of the components and the contact stresses experienced by the bearing materials. Errors of surgical technique such as component malalignment and malrotation can dominate any advantages of improved design or material wear resistance, increasing the chances of focal loading and increased wear. Acetabular component malpositioning can lead to impingement, which in turn can increase the wear of both the UHMWPE bearing surface, as well as the modular interface, within the metallic shell. Even careful attention to technique by high-volume, experienced arthroplasty surgeons cannot always prevent variability in knee implant kinematics, as revealed by fluoroscopic studies of joint motion that could result in accelerated wear.

Table 3:

Surgical Factors Affecting Joint Wear

Surgical Approach

Component Position

Restoration of appropriate mechanical and rotational axes

Initial stability and method of component fixation

Soft-tissue balance (laxity versus over constraint)

Subluxation or dislocation

Third-body wear

Surgeon Experience

Concerns have emerged that the newer, less invasive surgical approaches may diminish exposure and visualization and produce a new surgeon learning curve. This may increase the difficulties experienced in both hip and knee surgery in achieving optimal implant position and placement and avoiding iatrogenic implant surface damage. Regardless of exposure, iatrogenic third-body particulate–induced wear may be increased by suboptimal cementing technique, residual bone chips, or debris generated from instruments and implant insertion.

Evaluating surgical technique by studying implant position has been limited by two-dimensional radiographs, although computed tomography studies have been used to assess component rotation and occult osteolysis in selected problem cases. Computer-assisted surgical methods are evolving as a means of reliably achieving accurate soft-tissue balance and proper implant and limb alignment with fewer outliers. Eventually, computerized instrumentation systems may provide surgeons with meaningful kinematic data intraoperatively, which would be expected to lead to improved joint function and reduce wear. However, no clinical improvement in implant survivorship or patient outcomes has been demonstrated thus far with computer-assisted methods, with the possible exception of lower dislocation rates.

Larger diameters of femoral heads in total hip arthroplasties have been correlated with increased volumetric wear of conventional UHMWPE, while greater linear wear rates have been observed with smaller femoral head diameters. With the introduction of highly cross-linked polyethylenes and other alternative bearings, larger hip arthroplasty head sizes can be used without adversely affecting wear. Thus, head sizes 32-mm diameters are becoming more routine in the United States, except in those cases in which a small acetabular component is necessary. This shift has been prompted by hip-wear simulator experiments showing wear to be minimally affected by changes in head size up to 40 mm and showing newer, highly cross-linked polyethylene materials to be effective at insert thicknesses down to a few millimeters. Short-term clinical studies using highly cross-linked UHMWPE acetabular components have indeed shown reduced wear consistent with laboratory wear simulator data.

In total knee arthroplasty, the complex interaction of the tibia/femoral and patella/femoral bearing surfaces requires precise coronal, sagittal, transverse, and rotational alignment. Balancing the extensor mechanism to avoid patellar subluxation, tilt, excessive thickness, and/or patella baja or alta avoids increased contact stresses from impingement or maltracking. The complex kinematics of tibiofemoral motion can induce increased contact and subsurface stresses on the UHMWPE tibial insert due to subtle differences in mismatched component sizing, tibial spine or femoral cam impingement in posterior cruciate ligament–sacrificing designs, or increased shear stresses or impingement with imbalanced soft tissues.

Although the new materials available for hip and knee arthroplasty offer the promise of reduced wear, the population presenting for surgery has never been more challenging from an implant wear perspective. The balance between patient demand and concerns for wear and fixation has historically pushed the envelope for implant design, materials, and surgical technique. Future clinical studies will define the success of these efforts.

Outcome of surgical management of osteolysis in total hip arthroplasty (THA) is dependent on several factors. In the acetabulum and pelvis, factors affecting outcome include implant fixation and the ability to

retain the acetabular component; the size, location, and containment of the defects; and the extent of acetabular bone loss. When the implant components can be retained and the lesions can be treated, patient recovery is relatively quick. Because the implants are already osseointegrated, limited weight bearing is unnecessary. When acetabular component revision is required, a small but significant percentage of revision implants will not osseointegrated and may cause pain, requiring re-revision. Size, location, and containment of the defects are factors that, in part, determine the need for a bulk structural graft as opposed to impacted particulate bone graft. Clinical results in cases requiring only particulate grafting are better than those in cases that require a structural graft. Clinical outcomes are more predictable when sufficient host bone exists to allow the use of a porous-coated cages and structural allograft are required, outcome is usually compromised. In the femur, the factors that affect the outcome of surgical management of osteolysis are similar, including fixation of the implants and the ability to retain the stem, and the degree of femoral bone loss. Osseointegrated implants do not require postoperative activity restriction, and recovery is relatively quick. When femoral stem revisions required, a small but significant percentage of revision stems will not osseointegrated. With substantial proximal femoral bone loss and progressive widening of the diaphyseal canal, the ability to reliably obtain implant fixation is compromised

Rapid polyethylene wear and periarticular osteolysis were not frequently reported in association with all-polyethylene sockets inserted with cement in total hip arthroplasty. In contrast, the use of so-called “first-generation” porous-coated acetabular components without cement has resulted in an increased rate of polyethylene wear and an increased prevalence of osteolysis. Schmalzried et al. found so-called balloon like pelvic osteolysis in 17 per cent (nineteen) of 113 hips with a porous-coated titanium acetabular component. The mean thickness of the polyethylene in that series was approximately five millimeters in the dome and 3.5 millimeters in the periphery of the socket. Schmalzried et al. also noted that loss of bone was not generally associated with pain. There was no difference between the clinical scores of the patients who had pelvic osteolysis and those of the patients who did not. Researchers reported on fourteen patients (fifteen hips) who had pelvic osteolysis in association with a variety of porous-coated acetabular components inserted without cement. The mean time to presentation was sixty-five months. Despite the destructive nature of the lesions, fourteen of the fifteen sockets were stable and eleven of the fourteen patients had a Harris hip score of more than 90 points.

Analysis of the presenting symptoms in the current series is instructive. As has been reported previously, severe osteolysis can occur in the absence of clinical symptoms. Fourteen (40 percent) of thirty-five patients had no or only slight occasional pain in the hip at the time that the osteolysis and the polyethylene wear were noted. This finding emphasizes the need for postoperative surveillance of patients who have had a total hip replacement. Of the twenty-one patients who had pain before the revision, fifteen had an unstable femoral component, one had a spontaneous fracture of the greater trochanter, and one had pain related to subluxation. The remaining four patients had pain in the groin despite radiographically stable components. At the time of the revision, these four patients had marked synovitis of the hip, which may have caused the pain. When a patient has pain, it is important that other sources be sought, as polyethylene wear and osteolysis alone do not appear to cause pain.

The etiology of the osteolysis in the present study was a biological reaction to the high polyethylene particle load associated with rapid polyethylene wear. Proponents of acetabular revision for the treatment of this problem believe that complete debridement of the granuloma is essential in order to arrest this process. The premise is that a sustained particle load is a more important variable driving the osteolytic process. As a result, the believe that the replacement of the liner and elimination of the source of the high particle load was more important than removal of all of the granulation tissue from the osteolytic lesion.

Leaving the metal shell in place prevented complete debridement of the granuloma because it was difficult osteolytic defects continued to enlarge after the revision, thus supporting the hypothesis. Furthermore, one-third of the lesions resolved completely whether or not they had been filled with bone graft. Since this is a relatively new problem, information regarding optimum operative treatment is lacking. The timing of the revision operation, the operative procedure of choice, and the expected outcome are still not known. As previously noted, the initial approach to this problem was to revise the acetabular component and to fill the defects with bone graft.

This approach was re-evaluated when it became clear that removal of a well fixed acetabular component commonly resulted in additional loss of bone and, in some cases, pelvic fracture. In the present study, which included at least two years of follow-up, showed that the exchange of the liner and debridement of the osteolytic lesion, with or without bone-grafting, was a reliable alternative to revision of the socket. None of the acetabular components in the study loosened after the revision, and the osteolytic process appeared to be at least temporarily arrested by this procedure. Obviously, additional follow-up studies are needed to determine the long-term results of this procedure. Several criteria must be met in order for this procedure to be successful. The metal shell must be stable at the revision operation. If it is unstable, the component should be revised. The acetabular component has to be modular or the manufacturer of the implant has to be willing to make a custom liner. This requires careful preoperative planning to determine the manufacturer and the exact style of the implant in place.

Consultation with the manufacturer will help the surgeon to determine options for exchange of the liner. It is also important that the locking mechanism be intact and functioning so that the new liner is stable within the acetabular shell. If the locking mechanism is unstable, the component should be revised or, in some select cases, the liner can be cemented into the shell. The acetabular shell should be of sufficient diameter to permit insertion of a polyethylene liner of adequate thickness. With modular femoral components, it may be possible to downsize the femoral head to allow for a thicker polyethylene liner. Again, consultation with the manufacturer of the implant will help to determine the options for downsizing of the femoral head. If the femoral component is non-modular and has a thirty-two millimeter head and the acetabular component is relatively small, the liner may be only two to four millimeters thick. In this situation, the manufacturer may be unwilling to supply a replacement liner. If so, the acetabular component may need to be revised. If a replacement liner that is less than six millimeters thick is available, the surgeon needs to weigh factors, such as the age, activity level, medical condition, and life expectancy of the patient, to decide whether it is better to use a thin liner or to revise the component.

Dental Implants (Prosthetic Dentistry)

Dental implants are artificial tooth replacements used to counter tooth loss. The procedure is categorized as a form of prosthetic (artificial replacement) dentistry, though it also falls into the category of cosmetic dentistry as well. Dental implants are a predictable treatment modality validated by long-term research. 8k Dental implants have been used in Europe since the 1960s and were introduced into the United States in the early 1980s. The main benefits to the use of dental implants include: restoration of natural function, preservation of adjacent tooth structure, preservation of bone, provision of additional support, resistance to disease, and improved esthetics. In the United States, there has been a surge in the demand for dental implants among patients and dentists. More than 90% of general dentists in the United States today have restored implants or referred a patient for implant placement. The number of dental implants used in the United States increased more than 10-fold from 1983 to 2002. Today over 700,000 dental implants are inserted annually. Because of this increased demand; dental clinicians have many dental implant systems available to choose from. According to Jokstad et al., more than 220 implant brands have been identified

that are produced by about 80 manufacturers. Due to the highly mobile military populations and the need to standardize the serviceability of implants in all Air Force dental clinics, the practices of United States Air Force Dental Service (AFDS) limit dental implant systems to be placed in active duty patients to the procedures and implants consistent with the Nobel Biocare or Implant Innovations, Inc. (3i) product line or implants that are 100% compatible with these two systems. These particular implant systems have shown outstanding quality control, backed by evidence-based research, a track record of long-term business success with a full range of predictable clinical options available.

When treatment planning for a dental implant, practitioners must consider dental implant system selection, type of definitive restoration, and perceived maintenance following placement. Tooth restorations can range from replacement of one single tooth, to an entire arch, or as stabilizing elements over dentures. Implants are routinely placed by both military and civilian dentists including periodontists, oral and maxillofacial surgeons, general dentists, prosthodontists, and endodontists. Dental implants have various root forms, designs, dimensions, surfaces, and connectors. Several studies have shown that dental implants can be identified radiographically. When a patient presents for replacement of an existing implant-supported abutment or crown, the restorative dentist is challenged to first identify the existing implant. In the military, dentists will need to use radiographs to identify implants placed before entry into the service and must be familiar with detailed morphology of different products and types of fixtures.

Teeth are lost due to:

1. Tooth decay 2. Root canal failure 3. Periodontitis (gum disease) 4. Trauma to the mouth 5. Excessive wear and tear 6. Congenital defects

There are multiple factors that people may choose dental implants:

Cosmetic Emotional distress due to tooth deformity or loss Biting irregularities caused by tooth loss can have a negative effect on eating habits and this can

lead to secondary health problems like malnutrition.

Regardless of the nature of problems related to tooth loss, dental implants may provide a simple remedy with proven results. Dental implants are stronger and more durable than their restorative counterparts (bridges and dentures). Implants offer a permanent solution to tooth loss. Additionally, implants may be used in conjunction with other restorative procedures for maximum effectiveness. For example, a single implant can serve to support a crown replacing a single missing tooth. Implants can also be used to

Strong, durable and natural

in appearance, implants are

Among the most successful

dental procedures performed.

Before After

support a dental bridge for the replacement of multiple missing teeth, and can be used with dentures to increase stability and reduce gum tissue irritation.

Procedural advancements, including the development of narrower “mini” implants, mean that more people than ever before are finding themselves as candidates for implantation. However, candidacy for implantation still varies, only a dentist may determine that you should opt for an alternative restoration. Keep in mind that dentists do not need a specific license by law in order to perform implant dentistry. A general or restorative dentist may perform the crown and bridge placement that is associated with implant restoration. However, prosthodontists are the specialists who often complete this crucial procedure. Periodontists and oral surgeons perform the implant surgical procedure itself. Today's dental implants are virtually indistinguishable from other teeth. This appearance is aided in part by the structural and functional connection between the dental implant and the living bone. Implants are typically placed in a single sitting but require a period of osseointegration.

Osseointegration is the process by which direct anchorage of a dental implant root and the bone of the jaw occurs. Osseointegrated implants are the most commonly used and successful type of dental implant. An osseointegrated implant takes anywhere from three to six months to anchor and heal, at which point the dentist can complete the procedure with the placement of a crown. Once the implant has anchored with the jawbone, artificial prosthesis may be attached and the process is completed. If osseointegration does not occur, the implant will fail.

New research is helping to identify early biomarkers of prosthetic performance, as well as genetic polymorphisms that predict risk of osteolysis, according to new research presented at a joint session of the Orthopedic Research Society and the American Academy of Orthopaedic Surgeons (AAOS) during the annual meeting in Chicago, Illinois. Serum and urine levels of metal ions, biomarkers of bone metabolism, and collagen degradation can have diagnostic utility for predicting future implant failure, says Joshua J. Jacobs, MD, an orthopedic surgeon at Rush University Medical Center in Chicago, Illinois. Moreover, genomic studies looking at gene expression profiling may serve as a genetic fingerprint of loose or infected implants, he says.

Specifically, decreases in type-I C-terminal peptide (PICP) and increases in cross-linked amino-terminal telopeptide of type I collagen (NTx) may be markers of loose implants. Moreover, more than 8 parts per billion (ppb) of serum titanium can indicate that the implant is loose, that there are multiple implants, or that there is polyethylene wear-through and metal is rubbing on metal, among other possibilities. Markers of serum and urine collagen degradation may also serve as early markers of osteolysis and loosening well before symptoms appear, explains Dr. Jacobs.

Large-scale, long-term, controlled and prospective studies are needed to validate the clinical utility of these biomarkers; and, if validated, they may be powerful surrogate endpoints for clinical trials and have a significant clinical impact on the management of patients who are at risk for implant loosening or failure.

Mark J. Wilkinson, MB, ChB, PhD, of the Bone Metabolism Group in the division of clinical sciences at the University of Sheffield in Sheffeld, UK, has ongoing research in identifying genetic polymorphisms that increase or decrease risk of osteolysis. For example, polymorphisms in interleukin-1 and FRZB genes may decrease risk of osteolysis. Another aspect of this research is the potential development and use of gene panels to assess risks of osteolysis even before a patient undergoes arthroplasty. The new findings are a good first start in understanding the genetics of osteolysis.

The major implant markets are orthopedic, internal fracture fixation, cardiovascular, ophthalmic, and dental. The orthopedic implants consist of partial or total hip joint replacement, partial or total knee joint replacement, and of shoulder, elbow, and finger joints. The internal fracture fixation is considered to be part of orthopedic implant. Dental implants consist of the artificial tooth implant. The health of the aging population in the United States plays a crucial role in the growth of medical implants and the materials. The exposure about good health and fitness was not very high during the earlier years. It is only now that people have started prioritizing long and healthy life above all. Therefore, the older generations are facing a number of additional concerns in regards to their health including weakness of bones, degradation of

joints, and other orthopedic problems. These additional concerns are proving to have beneficial reasons for the growth and prosperity of the medical implants market.

The active lifestyle of people is a key propellant of the medical implants market. Today’s generation have increased energetic and fast-paced lifestyle. The decrease in leisure and relax time, not only affects the mental and emotional well being, but adversely effects the physical health of individuals. Majority working people tend to have increased medical complications and early aging of the physical body and bone structures due to their negligence. For instance, inappropriate sitting position at work and while driving may lead to adverse spinal problems at early ages. This problem may not have occurred if the person gave the body regular rest and healthy exercise. However, as most people have no time for regular rest and exercise the numbers of cases with the need for orthopedic, cardiovascular, and other implants have been increasing steadily and thereby creating positive growth for the market.

New materials and improvement in properties of materials are required for new implant applications. The major focus of the implant manufacturers is to develop implants which can be kept inside the body with minimal invasiveness and less impact on the patient. The development of minimally invasive implants requires materials that are stronger, more fatigue resistant, and highly biocompatible. For example nitinol due to its shape memory properties has enabled construction of self expandable stents that can be implanted with less trauma for the patient. Bioabsorbable polymer and magnesium based stents that degrade inside the body, after specific time, is expected to drive the cardiovascular stents market. The advent of new applications for these improved materials is expected to drive the materials market.

Many implant manufacturing companies have come up with products and implantation techniques that reduce the extent of invasiveness. Many companies have introduced unicompartmental knees and partial hip implant that need smaller incision than before. As these procedures reduce the trauma of the patients and enable them to go back to their active life sooner, many patients are willing to get implanted. The non-surgical treatment, such as taking drugs, injections, physical therapy, and/or other alternative treatments that may subside or decrease the pain, reduces the market for the implants. Many doctors advise the patients to go for implants only as the last resort when all other treatments fail or patient is not in a condition to take up those treatments. For many younger patients, doctors delay the implantation due to the present life of the current implants is less than the average life of the patients and may require secondary surgery to remove implant and revise a new one.

Improvements in biomaterials, implant and prosthetic design, better understanding of biomechanics, and improved imaging methods and surgical techniques have contributed greatly to the progress of orthopedic surgery. Orthopedic implants consist of total and partial replacement of hip and knee joints, spinal fusion cages and spinal disks, shoulder joints, elbow and finger joints replacement and implants that are used to treat problems in tendons, ligaments, and muscles. From the materials focus, major orthopedic implant markets researched in this study are hip, knee, shoulder and elbow, spinal, and trauma fixation. The present day hip or knee replacements can restore near normal function to patients with severe pain or markedly limited function. The number of individuals undergoing this type of surgery is anticipated to increase as the population continues to age and as the indications for joint arthroplasty extend to younger patients. For the majority of patients so treated, initial results following surgery are excellent.

Despite this success, implant wear remains the major problem facing the long-term success and survival of these artificial joints. Recent studies have shown that large amounts of minute wear particles are produced by these orthopaedic implants (both metal and plastic), setting into motion a cascade of events that ultimately may result in the disappearance of bone around the implant (osteolysis). This can lead to implant loosening and failure of the artificial joint. Surgery to replace these failures is more difficult to perform, is more costly, and has a poorer outcome than the original joint replacement surgery.The cartilage in between the hip ball and socket becomes damaged due to multiple diseases, such as osteoarthritis rheumatoid arthritis, and osteonecrosis. When the cartilage is damaged, the bones come into contact with each other and cause severe pain to the patients. Partial or total hip replacements are seen as an end stage treatment for this type of condition. A hip replacement is a surgical procedure whereby the diseased cartilage and bone of the hip joint is surgically replaced with artificial materials. The normal hip joint is a ball and socket joint. The socket is a cup-shaped bone of the pelvis called the acetabulum. The ball is the head of the thigh bone (femur). Total hip joint replacement involves surgical removal of the diseased ball and socket.

Table 4 and Figure 4 show the hip joint replacement procedure forecasts for the U.S. medical implant markets during the period 2002 to 2012.

Table 4

Figure 4

Approximately 320,436 total hip joint replacements were done in 2005 and this is expected to grow and reach 363,591 in 2012 at a CAGR of 1.8 percent between the period 2005 to 2012.

Osteoarthritis is the main cause for the requirement of knee joint replacement procedures. Partial or unicompartmental knee replacement is done to replace only the most damaged areas of the cartilage.

Partial knee joint replacement is comparatively a minimal invasive surgery. In case of total knee replacement, the articulating surfaces are fully replaced with metal and plastic. Knee joint replacement or arthroplasty procedures are broadly categorized as primary or revision. Primary and revision surgeries are either unicompartmental or total. Revision surgery of the knee is intended to restore the joint line, stability, and alignment of the knee joint through partial or total replacement of primary prosthetic knee components.

Preservation of quality bone stock is a high priority in revision procedures. Femoral part is resurfaced with a metal brace, the cobalt chromium alloys are the material of choice. Smith and Nephew have introduced Oxinium material for the femoral part and have achieved considerable success and it is expected to gain share in the market. The tibial articulating surface is resurfaced with a tibial tray; again cobalt chromium is the material of choice, and a plastic tibial insert to eliminate the friction between the metal parts. UHMWPE is the material of choice for the insert. Cross linked UHMWPE is being used as the wear resistant of this plastic is higher and hence produce lesser micro wear particles which ultimately loosens the implant as they are attacked by the white blood cells. Usage of PEEK is being considered as they offer better properties than UHMWPE.

Table 5 and Figure 5 show the hip joint replacement procedure forecasts for the U.S. medical implant markets during the period 2002 to 2012.

Table 5

Figure 5

Approximately 324,809 combined knee joint replacements were done in 2005 and this is expected to grow and reach 379,358 in 2012 at a CAGR of 2.2 percent.

Other Orthopedic Implants

The implants for shoulder, elbow, wrists, ankle, and maxillofacial reconstruction implants are in an increasing trend.

Table 6 and Figure 6 show the shoulder and elbow joint replacement procedures forecast for the U.S. materials in medical implant markets during the period 2004 to 2012.

Table 6. Medical Implant Markets: Shoulder and Elbow Joint Replacement Procedure Forecasts, 2004-2012

Figure 6. Medical Implant Markets: Shoulder and Elbow Joint Replacement Procedure Forecasts, 2004-2012

In 2005, 34,082 units of shoulder and elbow replacement procedures were done in the United States. It is likely to reach 59,619 units in 2012 and record a CAGR of 8.3 percent. The stem and ball of the shoulder and elbow are of single piece. The material of choice is a cobalt chromium alloy. Patients that may suffer from finger joint pain or dysfunction due to arthritis or traumatic injury and finger joint replacements are done to relieve the pain for these patients. In the case of fingers, silicone has been the material of choice for a long time. Finger implants restores between 30 and 40 degrees of motion compared to 90 degrees of natural finger but it enables the patients to do near normal activities. But other major disadvantages of silicone finger implants are implant fracture, implant dislocation, silicone synovitis, and host reaction.

Fracture treatment includes casting, internal fixation, and external fixation. The internal fixation is the focus of this study as it uses implants for fracture treatment. Internal trauma fixation implants are used for treatment of fracture of bones. By immobilizing the bone and its associated fragments, fixation implants helps to improve healing of the bone, reduce the risk of damage to nerves and blood vessels, and to help reduce pain. The internal trauma fixation implants includes intramedullary nails, plates and screws, cannulated screws, and pins and wires. Materials of choice for the internal fixation implants are stainless steel and titanium. The share of titanium is an increasing trend due to better biocompatibility, imaging friendly, and strength closer to bone. In addition, share of metal is decreasing as the usage of resorbables is increasing. The advantage of resorbable is that they degrade within the body over specified time and there is no need for revision surgery to remove the implant. The main drawback of resorbables is that they do not possess the compressive strength of metals and could not be used to treat load bearing bone fractures. There is tremendous research in this arena and it is hoped that the problem will be solved in near future. The other material being considered is the non resorbable carbon fibers which exhibit the strength of metals and at the same time provide resorbable benefits.

Intramedullary (IM) nails are long - cylindrical metal devices used to stabilize long bone fractures, usually transverse or short oblique midshaft fractures, and allow for healing. IM nails are inserted into the medullary canal in the center of long bones after the surgeon has usually reamed it to allow for insertion. The long bones include the femur, tibia, fibula, humerus, radius, and ulna, but specialty nails are also used to fuse the ankle and knee. The majority of nails are used in the femur or tibia, but the implants are also used in the treatment of fractures in other long bones as well. Ankle fusion nails are forecasted to experience the strongest growth of any anatomical area since they are relatively new to the market and have been positively accepted by surgeons for ankle arthrodesis.

Nails offer advantages over other fixation methods, such as faster bone healing times, lower infection rates, and earlier patient mobilization. IM nails share the load with the bone instead of simply supporting the bone across the fracture site as do plates. This allows patients to move sooner than if they were casted or plated thereby helping with postoperative rehabilitation. Nails are inserted through a relatively small incision at one end of the bone and do not require open surgery as does plating, helping to reduce blood loss, and the risk for infection. Yet, nails are only for use in long bones and are limited to treating certain fracture patterns. In addition, some patients complain of pain at the nail’s insertion site. In 2005, about 85.0 percent of intramedullary nails implanted in the United States were titanium, with the remaining nails made from stainless steel. The percent of nails that are titanium is expected to reach 91.8 percent share by 2012.

Table 7 and Figure 7 indicate the intramedullary nails forecast for the U.S. medical implant market for the period 2002 to 2012

Table 7

Figure 7

The major medical device participants are Smith & Nephew, Synthes-Stratec, Stryker Howmedica Osteonics, Biomet, Zimmer, Acumed, and Depuy ACE. Smith & Nephew had 32.0 percent market share in 2004 and is closely followed by Synthes-Stratec.

Plating has been the primary treatment for many serious fractures. In recent years, periarticular plates, which are those plates specially designed for use on fractures that occur close to joints such as the knee and hip, have become increasingly popular, as have other plate designs with low profiles and other features that allow for minimally invasive implantation. In general, bone plates are better suited for treating fractures in or around the joints, whereas IM nails are designed for treating segmental and shaft fractures. Plates are also used in non-load bearing areas and in the skull, spine, pelvis, feet, and hands where nails cannot be used. While plates provide direct reduction and rigid fixation, IM nails provide indirect reduction and allow for greater motion at the fracture site.

The majority of plates used in the United States are stainless steel, but some surgeons prefer titanium because of its better biocompatibility and imaging profile. Bone screws come in multiple designs, lengths, and diameters. The two major classifications are cortical and cancellous bone screws, which are design to be used with the respective types of bone. Cortical screws are used with plating systems and are therefore much more commonly used than cancellous screws. The majority of bone plates sold in the United States are made from stainless steel, but titanium is becoming increasingly popular. Facilities indicate that their preference for steel is primarily economic since it costs less and delivers all the sufficient strength and material properties that most surgeons require for their patients. Many manufacturers admit that when it comes to plating, titanium options are more of a marketing point rather than a clinical necessity. Interestingly, some manufacturers indicate that titanium is more preferred for use in craniomaxillofacial

procedures than in the rest of the skeleton. Around 64.0 percent of plates and screws sold in the United States in 2005 were stainless steel, and likely to decrease to 50.4 percent by 2012.

Table 8 and Figure 8 show the plate and screws forecast by material type for the U.S. medical implant market for the period 2002 to 2012.

Table 8

Figure 8

The plate and screw market unit shipment is expected to grow and record a CAGR of 7.1 percent between 2005 and 2012. The titanium plate and screw are expected to grow and record a CAGR of 12.1 percent between 2005 and 2012 whereas stainless steel plate and screw are expected to grow and record a CAGR of 3.5 percent between 2005 and 2012.

Projected HPMA Copolymer Diagnostic Agent Annual Revenue

The HPMA Copolymer Diagnostic Agent currently in preclinical development will compete in the contrast agent market. The unit pricing varies significantly from a modest price of $46.00 per unit for Omnipaque to a relatively more aggressive unit price of $ 142.50 for Isovue 300. Although it is anticipated that the HPMA Copolymer Diagnostic Agent will support a premium price point, for purposes of this initial analysis, the average of three of the mostly widely used comparable contrast agents was utilized. See the Table 9.

Table 9

Table 10 below depicts the projected procedures that will produce candidates for follow up testing utilizing the HPMA Copolymer Diagnostic Agent:

Table 10

In additon to the projected procedures that will produce candidates, approximately 20% will receive a series of follow up exams on 6, 12, 18, and 24 month basis utilizing the HPMA Copolymer Diagnostic Agent. This is reflected in the projected revenue depicted in the following Table 11 and Figure 9.

Table 11

Figure 9

Dental Implant Market Projected Revenues

Additional revenues are expected to be generated from the Dental Implant Market Segment

Table 12

Figure 10

Figure 11 Depicts the total projected HPMA Copolymer Diagnostic Agent Revenues

Figure 11

Table 13 below depicts the NPV and rNPV for the HPMA Copolymer Diagnostic Agent: