Narumichi Murakami

A biodegradable polymer as a cytokine delivery system for inducing bone formation

Bone morphogenetic proteins (BMPs) that have the potential to elicit new bone in vivo have been used in a tissue-engineering approach for the repair of bone injuries and bone defects. Although it is now possible to generate large amounts of recombinant human (rh) BMPs for medical use, the major challenge remains in the development of optimal local delivery systems for these proteins. Here we describe the development of a synthetic biodegradable polymer, poly-d,l-lactic acid–p-dioxanone–polyethylene glycol block copolymer (PLA-DX-PEG). This polymer exhibits promising degradation characteristics for BMP delivery systems and good biocompatibility under test conditions. PLA-DX-PEG/rhBMP-2 composite implants induced ectopic new bone formation effectively when tested in vivo, and can repair large bone defects orthotopically. This polymeric delivery system represents an advance in the technology for the enhancement of bone repair.

Carbon Nanotubes with High Bone‐Tissue Compatibility and Bone‐Formation Acceleration Effects

Carbon nanotubes (CNTs) have been used in various fields as composites with other substances or alone to develop highly functional materials. CNTs hold great interest with respect to biomaterials, particularly those to be positioned in contact with bone such as prostheses for arthroplasty, plates or screws for fracture fixation, drug delivery systems, and scaffolding for bone regeneration. Accordingly, bone-tissue compatibility of CNTs and CNT influence on bone formation are important issues, but the effects of CNTs on bone have not been delineated. Here, it is found that multi-walled CNTs adjoining bone induce little local inflammatory reaction, show high bone-tissue compatibility, permit bone repair, become integrated into new bone, and accelerate bone formation stimulated by recombinant human bone morphogenetic protein-2 (rhBMP-2). This study provides an initial investigational basis for CNTs in biomaterials that are used adjacent to bone, including uses to promote bone regeneration. These findings should encourage development of clinical treatment modalities involving CNTs.

Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers

The regenerating potential of human bone is limited. The repair of large bone defects often associated with bone tumor resections is not observed, and nonunion or delayed union of bone is a serious problem for fracture treatment. In these cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require invasive surgical procedures. An alternative approach described in this paper involves the injection of bone morphogenetic proteins (BMPs) in a polymeric delivery system. We demonstrate that synthetic biodegradable polymers, poly-D,L-lactic acid-polyethylene glycol (PLA-PEG) block copolymers, which exhibit an exquisite temperature-dependent liquid-semisolid transition, work well as an injectable delivery system for recombinant human (rh) BMP-2. The thermosensitive property of the PLA-PEG/rhBMP-2 composite is permissive to percutaneous injection when heated. The fluidity of this composite decreases as it cools down to body temperature and the resultant semisolid form provides a scaffold for bone formation through the gradual local release of the rhBMP-2. This new type of injectable osteoinductive material will enable a less invasive approach to surgeries involving the restoration or repair of bone tissues.

Biodegradable poly-D,L-lactic acid-polyethylene glycol block copolymers as a BMP delivery system for inducing bone.

Background: Bone morphogenetic proteins (BMPs) are biologically active molecules capable of eliciting new bone formation. In combination with biomaterials, these proteins can be used in a clinical setting as bone-graft substitutes to promote bone repair. Collagen from animal sources has previously been the preferred carrier material in animal experiments. More recently, synthetic biodegradable polymers have been tested as a delivery vehicle for osteoinductive agents. In earlier studies performed in our laboratory, it was found that the polylactic acid homopolymers (PLA650) and poly-d,l-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liquids that can be used as BMP delivery systems. Methods: To obtain new PLA-PEG polymers that exhibit greater plasticity, the molecular sizes of PLA and PEG segments in the copolymer chains were increased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ratios were synthesized, mixed with recombinant human (rh) BMP-2, and implanted into the dorsal muscles of mice for 3 weeks to evaluate their capacity to elicit new bone formation. To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bone area, and bone mineral density (BMD) of the ectopic new bone were measured by means of single energy X-ray absorptiometry (SXA). Results: All of the PLA6,500-PEG3,000 implants with 10 or 20 g of rhBMP-2 showed new bone formation. In contrast, little or no bone formation was seen in other plastic PLA-PEG implants with rhBMP-2. Control implants that lacked rhBMP-2 did not show new bone formation. Radiographic and histologic examinations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks after implantation had normal bone characteristics with hematopoietic marrow and osseous trabeculae. SXA analysis showed that the values for bone mineral content (BMC), bone area, and bone mineral density (BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000 polymers with rhBMP-2 were significantly higher than those obtained with the liquid PLA650-PEG200 polymers (p < 0.001 for each of the three values). Conclusions: These results indicate that the PLA6,500-PEG3000 block copolymer with plastic properties works effectively as a BMP delivery system. These data suggest that the total molecular size and ratio of PLA size to PEG size is an essential factor in determining the efficacy of a BMP delivery system. After implantation, it is possible that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids and become swollen, resulting in bone formation that exceeded the size of the original implants. This expansion characteristic is a potentially beneficial property, given the intended practical application of the polymer in the repair of bone defects.Clinical Relevance:New synthetic biodegradable delivery systems will play an important role in the clinical applications of rhBMPs in which local formation of bone via an osteoinductive graft material is needed. Further pre-clinical and clinical work is necessary to establish the safety of these implants before they are adopted for widespread clinical use.

Atrophy of the Deltoid Muscle Following Rotator Cuff Surgery

BACKGROUND Less invasive procedures have recently been introduced to facilitate an earlier return to sports or work activities after rotator cuff repair. Few reports, however, have verified whether such procedures are really less invasive than conventional open repair. The purpose of this study was to compare the postoperative thickness of the deltoid muscle in patients treated with either conventional or mini-open rotator cuff repair. METHODS Conventional open repair was performed from 1994 through 1997 in forty-three patients with rotator cuff tears. The mini-open deltoid-splitting approach was introduced in 1997, and the cases of thirty-five patients who underwent that procedure were reviewed. The two groups were compared with respect to the thickness of the anterior fibers of the deltoid muscle measured on the transverse magnetic resonance images, the degree of active forward flexion, and the times required for return to work and sports activities. RESULTS The thickness of the anterior deltoid fibers did not change significantly after surgery in the mini-open repair group, whereas it was significantly decreased in the open repair group at six months as well as at twelve months postoperatively (p < 0.05). At three months postoperatively, the mean University of California at Los Angeles score for active forward flexion in the patients treated with the mini-open repair (4.9 points) was significantly greater than that in the patients in the conventional open repair group (4.6 points) (p < 0.05). In addition, the mean time-period required for return to work in the mini-open repair group (2.4 months) was significantly shorter than that required in the control group (3.4 months) (p < 0.05). CONCLUSIONS The mini-open repair appeared to cause less postoperative atrophy of the deltoid muscle than did the conventional open rotator cuff repair, and patients treated with the mini-open repair recovered more quickly.

Analysis of pelvic movement in the elderly during walking using a posture monitoring system equipped with a triaxial accelerometer and a gyroscope

The incidence of falls in the elderly is increasing with the aging of society and is becoming a major public health issue. From the viewpoint of prevention of falls, it is important to evaluate the stability of the gait in the elderly people. The pelvic movement, which is a critical factor for walking stability, was analyzed using a posture monitoring system equipped with a triaxial accelerometer and a gyroscope. The subjects were 95 elderly people over 60 years of age. The criteria for instability were open-eye standing on one leg for 15s or less, and 11s or more on 3m timed up and go test. Forty subjects who did not meet both of these criteria comprised the stable group, and the remaining 55 subjects comprised the unstable group. Pelvic movement during walking was compared between the two groups. The angle, angular velocity, and acceleration were analyzed based on the wave shape derived from the device worn around the second sacral. The results indicated that pelvic movement was lower in all three directions in the unstable group compared to the stable group, and the changes in the pelvic movement during walking in unstable elderly people were also reduced. This report is the first to evaluate pelvic movement by both a triaxial accelerometer and a triaxial gyroscope simultaneously. The characteristics of pelvic movement during walking can be applied in screening to identify elderly people with instability, which is the main risk factor associated with falls.

Magnetic Resonance Imaging Staging to Evaluate the Stability of Capitellar Osteochondritis Dissecans Lesions

Background: Treatment for capitellar osteochondritis dissecans (COCD) lesions is usually based on their stability from the bony floor after arthroscopic or open direct observation. Thus, a noninvasive means of lesion stability assessment by use of imaging is desirable to preoperatively determine treatment strategy. Purpose: To evaluate our modified MRI staging system for COCD, we compared the results of MRI staging with the International Cartilage Repair Society (ICRS) classification for lesion stability. Intra- and interrater reliability for MRI staging was examined as well. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Fifty-two COCD lesions were preoperatively evaluated by T2-weighted MRI and classified into 5 stages: stage 1 = normally shaped capitellum with several spotted areas of high signal intensity that is lower than that of cartilage; stage 2 = as with stage 1 but with several spotted areas of higher intensity than that of cartilage; stage 3 = as with stage 2 but with both discontinuity and noncircularity of the chondral surface signal of the capitellum and no high signal interface apparent between the lesion and the floor; stage 4 = lesion separated by a high intensity line in comparison with cartilage; and stage 5 = capitellar lesion displaced from the floor or defect of the capitellar lesion noted. The MRI staging results were compared with the intraoperative ICRS classification for lesion stability of each patient. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were all determined for fragment instability. Intra- and interrater correlations for our MRI staging were calculated among 3 examiners. Results: Preoperative MRI grading correctly matched ICRS classification in 49 of 52 patients (94%), with a sensitivity of 100% and a specificity of 80%. The PPV and NPV were 93% and 100%, respectively, for diagnosing lesion instability. Intrarater reliability (intraclass correlation coefficient [ICC]) for MRI staging was high at ICC(1, 1) = 0.86 and ICC(1, 2) = 0.90, as was interrater reliability at ICC(2, 1) = 0.82 and ICC(2, 3) = 0.88. Conclusion: The MRI staging system provides accurate and reliable evidence for estimating ICRS classification and instability of COCD and is useful to decide appropriate treatment.

The two locations of ganglions causing radial nerve palsy.

Ganglions associated with radial nerve palsy at two different locations were identified at the elbow in 14 patients. The first type, found in 13 patients, arose from the anterior capsule of the proximal radioulnar joint and was located proximal to the proximal edge of the supinator muscle. It compressed the main radial nerve anteriorly. The second type, which has not been reported before in patients without abnormalities in the elbow joint, was found in the remaining patient. It was located in the supinator muscle, distal to the proximal edge of the supinator muscle, and compressed the posterior interosseous nerve against the proximal radius. Magnetic resonance imaging makes it possible to identify ganglions in a wide area around the elbow. This examination should be carried out in view of the possible presence of both types of ganglion. Magnetic resonance imaging also provides more accurate information than computed tomography or ultrasonography about the location and characteristics of the mass.

Extensor Tendon Rupture Associated with Osteoarthritis of the Distal Radioulnar Joint

Non-rheumatoid osteoarthritis of the distal radioulnar joint can cause extensor tendon rupture. We analysed the radiographic morphology of the distal radioulnar joint to identify the risk factors for this complication. Forty-one wrist X-rays of 37 patients with extensor tendon rupture caused by distal radioulnar joint osteoarthritis were evaluated retrospectively for the severity of osteoarthritis by the Kellgren/Lawrence scoring system. Measurements were obtained from posteroanterior views. All but one wrist had severe osteoarthritic changes exceeding grade 3. The radiographic features that were different from those of the contralateral wrists included deepening and widening of the sigmoid notch, radial shift of the ulnar head and dorsal inclination of the sigmoid notch. There was no significant association between tendon rupture and the morphology of the ulnar head or ulnar variance. The scallop sign, dorsal inclination of the sigmoid notch and radial shift of the ulnar head are radiological risk factors for extensor tendon ruptures.

Callus resection for brachial plexus compression following stress-induced first rib fracture.

A 27-year-old man presented with a lower trunk brachial plexus injury due to excessive callus formation following a stress-induced first rib fracture. The callus, but not the first rib, was resected through a supraclavicular approach. His symptoms resolved in 2 months, and no recurrence was seen at 2 years follow-up.