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We studied kinetics of biotransformation synthetic implant for substituting defects of the bone tissue using methods of computer tomography, scintigraphy and morphology in vivo and in vitro. We found that the character of biotransformation is dependent on the degree of loaded or unloaded bone tissue.
The purpose of this prospective study was to evaluate whether the shorter degradation time of the second-generation Meniscus Arrow would be adequate to allow meniscal healing and whether equally good results could be achieved compared to the first generation implant. We also wanted to assess whether some of the implant related complications could be avoided with the altered absorption time. A total of 20 patients were included in this study. The mean follow-up was 26 months. The average Lysholm score at the final follow-up was 90. There were 13 second-look arthroscopies performed during the follow-up and in them two failures of the repaired menisci to heal were seen. Seven patients were found with some degree of chondral irritation of the femoral condyle corresponding to the repair site. The second generation Meniscus Arrow seems to give results comparable to the first generation Meniscus Arrow. The potential complications caused by the implant reported in the earlier literature using the first generation arrow are possible also using this implant. In seven of the 13 second-look arthroscopies some degree of chondral irritation corresponding to the repair site was seen. The clinical relevance of these lesions remains to be seen.
The use of a novel injectable biocompatible and biodegradable camptothecin-polymer implant for sustained intra-tumoral release of high concentrations of camptothecin is described. The drug delivery vehicle is an in situ thermogelling formulation, which is based on the natural biopolymer chitosan. This formulation, containing homogeneously dispersed camptothecin, was implanted intra-tumorally into a sub-cutaneous mouse tumor model (RIF-l). The effectiveness of treatment was measured in terms of tumor growth delay (TGD). Animals treated with the polymer implants containing camptothecin had significantly longer TGDs compared to untreated animals as well as to animals treated systemically with camptothecin by intra-peritoneal injection with no evidence of toxicity in terms of loss of body weight. The results indicate that this novel biodegradable polymer implant is an effective vehicle for the sustained intra-tumoral delivery of camptothecin which might also be suitable to deliver other insoluble anti-cancer drugs such as taxol.
The in vivo local reaction of as-polymerized poly-L-lactide composed of 96% L-lactide and 4% D-lactide (PLA96) was investigated by histology at 2, 13 and 26 weeks after subcutaneous implantation in rats. In order to simulate possible end stage reactions the PLA96 was also predegraded in vitro until approximately 50% weight loss. The local reaction of predegraded PLA (PLA96(168)) was compared to the local reaction of polyethylene (PE) and non-predegraded PLA (PLA96). For PE and PLA96 a mild local reaction was observed at all time points consisting of a minimal layer of macrophage like cells with incidentally multinucleated giant cells at the implant interface, surrounded by a mild connective tissue capsule. For PLA96 at weeks 13 and 26 some minimal alterations in terms of degradation and ingrowth of cells was noted. The in vitro incubation (90 degrees C for 168 h) of PLA96(168) resulted for the thin 0.2 mm samples in complete degradation. Predegraded 0.5, 1.0 and 2.0 mm PLA96(168) samples were implanted and evaluated. The 1.0 and 2.0 mm samples could be evaluated for all time points investigated, but some 0.5 mm PLA96(168) samples were already completely resorbed at week 2 after implantation. In general, responses found for the predegraded PLA96(168) at weeks 2, 13 and 26 were similar with a pronounced macrophage infiltrate containing birefringent material, encapsulation of polymer fragments, and the presence of a debris area consisting of polymer and cellular remnants. In lymph nodes foamy macrophages with birefringent material were only observed in lymph nodes draining sites with predegraded PLA96(168). Immunohistochemistry was performed for further characterization of the cellular infiltrate. At the implant interface of the non-degrading PE and PLA96, ED1 and OX6 (MHC class II) positive cells were identified. In the capsule macrophage like cells expressed all three macrophage markers ED1, ED2, and ED3. CD4 and CD8 positive cells, indicating T helper and T supressor/cytotoxic cells, respectively, could be observed in low numbers, CD4 more than CD8. Both CD4 and CD8 were occasionally observed within the degrading PLA96(168) implant. Polymorphonuclear neutrophilic granulocytes were mainly observed at 2 weeks after implantation. We showed that predegradation could be used as a means to study late tissue reactions to polymers. Complete degradation may be studied with relatively thin implants, but this may lead to rather optimistic interpretation of resorption periods. When materials are intended to be used for screws and/or plates for bone fixation, implants of at least 1.0-2.0 mm thickness should be used as these may show a more realistic representation of the resorption characteristics of the material under investigation.
This study examined the ability of NeuroGel, a biocompatible porous poly [N-(2-hydroxypropyl) methacrylamide] hydrogel, to establish a permissive environment across a 3 mm gap in the cat spinal cord in order to promote tissue reconstitution and axonal regeneration across the lesion. Animals with NeuroGel implants were compared to transection-only controls and observed for 21 months. The hydrogel formed a stable bridge between the cord segments. Six months after reconstructive surgery, it was densely infiltrated by a reparative tissue composed of glial cells, capillary vessels and axonal fibres. Axonal labelling and double immunostaining for neurofilaments and myelin basic protein, showed that descending supraspinal axons of the ventral funiculus and afferent fibres of the dorsal column regenerated across the reconstructed lesion. Fifteen months after reconstructive surgery, axons had grown, at least, 12 mm into the distal cord tissue, and in the rostral cord there was labelling of neurons of the intermediate gray matter. Electron microscopy showed that after 9 months, most of the regenerating axons were myelinated, principally by Schwann cells. Newly formed neurons presumably from precursor cells of the ependyma and/or migrating neurons were observed within the reparative tissue after 21 months. Results indicate that functional deficit, as assessed by treadmill training, and morphological changes following double transection of the spinal cord can be modified by the implantation of NeuroGel. This technology offers the potential to promote the formation of a neural tissue equivalent via a reparative neohistogenesis process, that facilitates and supports regenerative growth of axons.
BACKGROUND: Biodegradable implants have not been used on a large scale for internal fixation of mandibular fractures because of presumed inferior mechanical properties. This prospective clinical trial was designed to elucidate the stability and biocompatibility of self-reinforced poly-L/D-lactide plates and screws used to stabilize a variety of mandible fractures by open reduction and internal fixation. METHODS: Sixty-six consecutive patients (22 female, 44 male; mean age, 23.9 years) with a total of 89 fractures at various sites of the mandible were included in the study. Stability of plates and screws and bone healing were observed by clinical and radiographic assessment. Intermaxillary fixation was applied in eight patients with concomitant condylar fractures for 2 to 3 weeks. RESULTS: The self-reinforcement technique provided sufficient mechanical stability of the implants for primary healing of these high-load mandibular bone areas. Postoperative complications were transient and limited to wound dehiscence and localized wound infection (two patients). In some patients, hypesthesia (three patients) or slight pain (10 patients) was reported at the 1-year recall examination, but implant-related serious adverse tissue reactions were not observed during the follow-up (mean, 24.4 months; range 6.4 to 44.3 months). CONCLUSIONS: On the basis of these preliminary results, the authors conclude that biodegradable self-reinforced implants show efficient stability during initial bone healing and promise a high potential for successful use in osteofixation of mandibular fractures.
OBJECTIVES: Cyclopentenone prostaglandins have been shown to promote osteoblast differentiation in vitro. The aim of this study was to examine in a rat model the effects of local delivery of Delta(12)-prostaglandin J(2) (Delta(12)-PGJ(2)) on new bone formation and growth factor expression in (i) cortical defects and (ii) around titanium implants. MATERIAL AND METHODS: Standardized transcortical defects were prepared bilaterally in the femur of 28 male Wistar rats. Ten microliters of Delta(12)-PGJ(2) at 4 concentrations (10(-9), 10(-7), 10(-5) and 10(-3) mol/l) in a collagen vehicle were delivered inside a half-cylindrical titanium chamber fixed over the defect. Contralateral defects served as vehicle controls. Ten days after surgery, the amount of new bone formation in the cortical defect area was determined by histomorphometry and expression of platelet-derived growth factor (PDGF)-A and -B, insulin-like growth factor (IGF)-I/II, bone morphogenetic protein (BMP)-2 and -6 was examined by immunohistochemistry. In an additional six rats, 24 titanium implants were inserted into the femur. Five microliters of carboxymethylcellulose alone (control) or with Delta(12)-PGJ(2) (10(-5) and 10(-3) mol/l) were delivered into surgically prepared beds prior to implant installation. RESULTS: Delta(12)-PGJ(2) (10(-5) and 10(-3) mol/l) significantly enhanced new bone formation (33%, P<0.05) compared with control cortical defects. Delivery of Delta(12)-PGJ(2) at 10(-3) mol/l significantly increased PDGF-A and -B and BMP-2 and -6 protein expression (P<0.05) compared with control defects. No significant difference was found in IGF-I/II expression compared with controls. Administration of Delta(12)-PGJ(2) also significantly increased endosteal new bone formation around implants compared with controls. CONCLUSION: Local delivery of Delta(12)-PGJ(2) promoted new bone formation in the cortical defect area and around titanium implants. Enhanced expression of BMP-2 and -6 as well as PDGF-A and -B may be involved in Delta(12)-PGJ(2)-induced new bone formation.
A stent is a medical device designed to serve as a temporary or permanent internal scaffold to maintain or increase the lumen of a body conduit. Metallic coronary stents were first introduced to prevent arterial dissections and to eliminate vessel recoil and intimal hyperplasia associated with percutaneous transluminal coronary angioplasty. The stent application range has expanded as more experience was gained, and encouraging results have been obtained in the treatment of vascular diseases. Stents are currently used for support of additional body conduits, including the urethra, trachea, and esophagus. The rationale for bioresorbable stents is the support of a body conduit only during its healing process. The stent mass and strength decrease with time, and the mechanical load is gradually transferred to the surrounding tissue. Bioresorbable stents also enable longer term delivery of drugs to the conduit wall from an internal reservoir and abolish the need for a second surgery to remove the device. The present review describes recent advances in bioresorbable stents, focusing on drug-eluting bioresorbable stents for various applications. Controlled release of an active agent from a stent can be used to enhance healing of the surrounding tissues, to increase the implant's biocompatibility, as well as to help cure certain diseases. Because a lot of research in this field has been done by us, examples for these functions are described based mainly on developments in our laboratories.
BACKGROUND: Tissue engineering is a new approach in which techniques are being developed to transplant autologous cells onto biodegradable scaffolds to ultimately form new functional autologous tissue. Workers at our laboratory have focused on tissue engineering of heart valves. The present study was designed to evaluate the implantation of a whole trileaflet tissue-engineered heart valve in the pulmonary position in a lamb model. METHODS AND RESULTS: We constructed a biodegradable and biocompatible trileaflet heart valve scaffold that was fabricated from a porous polyhydroxyalkanoate (pore size 180 to 240 microm; Tepha Inc). Vascular cells were harvested from ovine carotid arteries, expanded in vitro, and seeded onto our heart valve scaffold. With the use of cardiopulmonary bypass, the native pulmonary leaflets were resected, and 2-cm segments of pulmonary artery were replaced by autologous cell-seeded heart valve constructs (n=4). One animal received an acellular valved conduit. No animal received any anticoagulation therapy. Animals were killed at 1, 5, 13, and 17 weeks. Explanted valves were examined histologically with scanning electron microscopy, biochemically, and biomechanically. All animals survived the procedure. The valves showed minimal regurgitation, and valve gradients were <20 mm Hg on echocardiography. The maximum gradient was 10 mm Hg with direct pressures. Macroscopically, the tissue-engineered constructs were covered with tissue, and there was no thrombus formation on any of the specimens. Scanning electron microscopy showed smooth flow surfaces during the follow-up period. Histological examination demonstrated laminated fibrous tissue with predominant glycosaminoglycans as extracellular matrix. 4-Hydroxyproline assays demonstrated an increase in collagen content as a percentage of native pulmonary artery (1 week 45.8%, 17 weeks 116%). DNA assays showed a comparable number of cells in all explanted samples. There was no tissue formation in the acellular control. CONCLUSIONS: Tissue-engineered heart valve scaffolds fabricated from polyhydroxyalkanoates can be used for implantation in the pulmonary position with an appropriate function for 120 days in lambs.
In this work the results of autopsy are presented--of a 45 years old man who died because of complications of cirrhosis in 24 months after repairing a postoperative hernia with the Matapurkar's "peritoneal sandwich" and polypropylene mesh. Macroscopically and histopathologically it has been shown that gradual healing of the mesh ends with formation of alloplastic-tissue connective structure, called neofascia that fills in the defect in fascia of the abdominal wall. Inflammatory process around implanted mesh maintains even after several months. It seems that parietal peritoneum of hernia sac that surrounds polypropylene mesh may have a tendency towards metaplasia in the direction of tissue-connective fascia layer.
Late, clinically manifest, adverse inflammatory reactions have sometimes occurred after the use of slowly degrading bioabsorbable poly-l-lactide (PLLA) devices in clinical series of bone fixation. In this study, long-term tissue response to bioabsorbable fracture fixation screws made of poly-l-lactide and to similar metallic screws in cancellous bone was examined and compared with intact bone. The postoperative evaluation of the rabbit femora was performed by using plain radiography, microradiography, histology, histomorphometry, and oxytetracycline labeling studies. The follow-up times were 36 and 51 months in groups of 15 and 14 rabbits, respectively. A walling-off response by formation of trabecular bone which outlined the screw profile was observed in the PLLA and metallic groups both. Connective tissue between this bone front and the implant was seen only in the PLLA group. There was no difference in the thickness of the layer between the two follow-up groups. Between the surgically handled femora and the intact control bone, there was no statistically significant difference in the amount of trabecular bone. The osteoid formation activity in the tissue-implant interface showed no differences between the groups. However, active osteoblasts were visible only in the PLLA group. The amount of birefringent PLLA material diminished between the 36-month and the 51-month follow-up groups. Within the follow-up times of this study, both the PLLA screws and the metallic screws were rather inert. Also, long-term walling-off was a typical response to both PLLA and metallic screws in cancellous bone. PLLA screws did not evoke any osteostimulatory reaction over the long-term follow-up. The findings clearly demonstrated that the overall degradation process of PLLA was very slow and accompanied by fibrous tissue formation. Macrophage activity seemed to be related to the slow degradation process of PLLA and might be associated with the formation of connective tissue replacing the original implant. The results of this study showed no significant differences between the bioabsorbable PLLA screws and the metallic screws in biocompatibility, and no signs of inflammatory foreign-body reactions occurred during the follow-up.
The recent identification of neurotrophic factors, such as the glial cell line derived neurotrophic factor (GDNF), acting on mesencephalic dopaminergic neurons, offers the possibility to stimulate the axonal regeneration of these cells which are affected in Parkinson's disease. Nevertheless, a safe and efficient GDNF delivery system that may be used in clinical trials is still lacking. We have developed GDNF-releasing microspheres capable of releasing the neurotrophic factor for at least 2 months in vivo. In this study we demonstrate that these microspheres, when implanted in the brains of 'Parkinsonian' rats, were well tolerated, and were able to induce sprouting of the preserved dopaminergic fibers with synaptogenesis. Moreover, this neural regeneration was accompanied by functional improvement. The implantation of GDNF-releasing microspheres could be a promising strategy in the treatment of Parkinson's disease.
PURPOSE: To fabricate and characterize in vitro and in vivo performance of a sustained release biodegradable implant for N-4-(benzoylaminophenylsulfonyl glycine) (BAPSG), a novel aldose reductase inhibitor. METHODS: The ability of BAPSG to inhibit aldose reductase activity and glucose-induced vascular endothelial growth factor (VEGF) expression was assessed in a retinal pigment epithelial cell line (ARPE-19). A poly (DL-lactic-co-glycolic acid) implant containing 50% w/w BAPSG was fabricated and characterized for drug loading, in vitro drug release, and the thermal behavior of the drug and the polymer. Implants were injected subcutaneously into a galactose-fed diabetic rat model and cataract scores, plasma and tissue drug levels, galactitol levels in the lens and the retina, glutathione levels in the plasma, lens, cornea and retina and VEGF expression in the retina were determined on or until 18 days. RESULTS: BAPSG inhibited aldose reductase activity and reduced VEGF expression in ARPE-19 cells. Implants (1 x 4 mm), with a loading efficiency of 106 +/- 7% for BAPSG, were fabricated. Upon implant fabrication, while the glass transition temperature of the polymer decreased, the melting point of the drug was not affected. In vivo drug release correlated well with in vitro release, with approximately 44% drug release occurring in vivo by the end of 18 days. The implant reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats. CONCLUSIONS: An injectable biodegradable implant of BAPSG sustained drug release in vitro and in vivo, and reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats.
We propose a large animal model for bone tissue engineering that yields quantitative data and simulates clinical methods and tissue needs. Skeletally mature domestic sheep (n = 20) were each implanted with three rectangular (1 x 1 x 4 cm), hollow tissue-molding chambers that were empty (control) or filled with equal weights (6.71-6.78 g) of particulate autologous bone graft (MBG) or bone graft that was autoclaved to denature stored growth factors (DeMBG). MBG provided scaffold and bioactive factors, and DeMBG provided only scaffold. The chambers were enclosed on five sides and securely implanted so that the open face was apposed to the osteogenic (i.e., cambium) layer of the rib periosteum for 3, 6, 9, 12, or 24 weeks, after which the chambers were harvested and the contents analyzed. Each chamber contained osseous and fibrovascular tissue. MBG-containing chambers had the best maintenance of tissue volume compared with DeMBG-containing or empty chambers, but it still decreased steadily over time. Despite this, the MBG-containing chambers showed continuous active bone formation. There was increasing calcified tissue with penetration of osteogenesis up to a mean of 0.75 +/- 0.15 cm from the periosteum by 9 weeks, and the osteogenic area peaked at 0.59 +/- 0.13 cm2 by 12 weeks. Using quantitative measures that reflect clinical needs (i.e., tissue volume, shape, and quality), it was possible to distinguish differences in performance associated with manipulation of implanted scaffold and bioactive factors. This ovine model may serve as a useful tool to develop clinical osseous tissue-engineering strategies.
This study evaluated the influence of recombinant human bone morphogenetic protein 2 (rhBMP-2) on the development and eruption of the secondary dentition. Primary premolar tooth extraction sockets in 12 16-week-old felines were implanted with either rhBMP-2, in collagen sponge or with buffer/absorbable collagen sponge (ACS). Unoperated jaw quadrants served as controls. Experimental conditions were randomized between jaw quadrants in all animals. Two animals receiving rhBMP-2/ACS and buffer/ACS in two quadrants per implant were sacrificed at 4 weeks postsurgery. Ten animals receiving rhBMP-2/ACS (two quadrants), buffer/ACS implants (one quadrant), and one quadrant serving as an unoperated control were evaluated at 12 weeks postsurgery. Clinical assessments included healing, eruption patterns, and crown development. Radiographic assessments included tooth development, eruption patterns, and bone formation. Histological observations were also made from the 4-week animals. The secondary dentition remained unerupted at 4 weeks postsurgery. Histological analysis showed normal alveolar bone coronal to the erupting teeth in rhBMP-2/ACS-implanted quadrants. At 12 weeks postsurgery, all teeth were erupted without differences between quadrants. Clinically, the crowns of all teeth were normal. Radiographs suggested that teeth in rhBMP-2/ACS- and buffer/ACS-implanted jaw quadrants exhibited similar tooth development and eruption patterns as the normal control. The evidence from this study suggests that surgical implantation of rh-BMP-2/ACS in the pathway of the developing and erupting secondary dentition does not interfere with the normal development and eruption patterns of the teeth.
This article provides an overview of the evolution of revascularization devices since Grüntzig's initial introduction of balloon angioplasty in 1977. In-stent restenosis (ISR) is the major shortcoming of conventional (permanent-implant) stent therapy; even with the innovation and promising benefits of drug-eluting stents, management of ISR is very difficult. ISR is mainly caused by the interaction between the blood and the stent surface and a permanent mechanical irritation of the vascular tissue. Thus stenting technology has moved toward the development of temporary implants composed of biocompatible materials which mechanically support the vessel during the period of high risk for recoil and then completely biodegrade in the long term. Preclinical and first clinical experiences with bioabsorbable magnesium stents are discussed.
PURPOSE: The purpose of this study is to follow myocardial angiogenesis temporally using quantitative magnetic resonance first pass perfusion imaging and compare this with the "gold standard" of radioactive microspheres in a random subset of animals. MATERIALS AND METHODS: Ameriod constrictors were placed around the left circumflex in 15 pigs to induce an ischemic area. Two groups were randomized to receive either a sham operation or treatment with angiogenic implants inserted into myocardium in the distribution of the left circumflex artery (LCX). These implants are designed to induce myocardial angiogenesis. Magnetic resonance first pass perfusion imaging was performed at baseline and also after treatment with either sham or implant therapy by using first pass perfusion imaging with a TurboFLASH sequence. Absolute myocardial blood flow was derived by applying a quantitative Fermi function model. Radioactive microspheres were also injected into a random subset of animals to measure myocardial blood flow. RESULTS: Angiogenic implant therapy increased absolute myocardial blood flow in the left circumflex territory relative to baseline and sham treated groups during adenosine infusion. Myocardial blood flows measured with radioactive microspheres was increased significantly in both the LCX and LAD territories during stress. Myocardial Perfusion reserve was also significantly increased in both the LCX and left anterior descending territories relative to baseline. Ejection Fraction during stress with dobutamine infusion increased significantly in the implant therapy group while that in the sham group was not affected. CONCLUSION: Quantitative MR myocardial first pass perfusion imaging can be used to track the development of angiogenesis as corroborated by radioactive microspheres. Angiogenic implant therapy is a new device based therapy that has potential to protect an ischemic region by accelerating angiogenesis although further research is necessary with this device.
The goal of this study was to develop ocular scleral implants able to release triamcinolone acetonide (TA) overall several months. Scleral discs were manufactured by a compression-molding method using a new synthetic polymer, poly(methylidene malonate) (PMM2.1.2), as matrix. Implants with good mechanical properties adapted for in vivo implantation have been obtained when using high M(w) PMM2.1.2 (100,000 - 150,000 Da) associated with ethoxylated derivatives of stearic acid (Simulsol) or oligomers of methylidene malonate as plasticizer. After implantation in rabbit eyes, scleral implants showed a good ocular biocompatibility. Indeed, the clinical follow-up and ocular inflammation parameters, such as inflammatory cell number and protein content in aqueous humor, demonstrated that implants were well tolerated and did not provoke abnormal inflammation. Implants were able to release significant concentrations of TA in the vitreous and the sclera throughout 5 weeks.