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Parathyroid hormone (PTH) exerts multiple effects such as regulating bone remodeling, promoting angiogenesis, etc., and it is an active factor with great application potential for bone repair. In recent years, with the development of scaffold material loading strategies and parathyroid hormone-related peptides (PTHrPs), in situ loading of PTH or PTHrPs on scaffold materials to promote bone defect healing gradually becomes possible. Based on the current status and challenges of intermittent PTH (iPTH) for bone tissue engineering, the review summarizes the in-situ application strategies of PTH and the construction of PTHrPs as well as current problems and further directions in this field, with a view to propel the clinical application of scaffold materials loaded with PTH or PTHrPs
Subject(s)
Bone and Bones , Parathyroid Hormone , Tissue Engineering , Tissue Scaffolds , Wound HealingABSTRACT
BACKGROUND: The local application of growth factor provides a promising therapeutic strategy for the treatment of refractory bone defects. However, there are still many factors that limit the application of the local growth factor delivery system, for example, inability to accurately control the amount of growth factors released and the low biological activity of the released growth factors. OBJECTIVE: To summarize a variety of growth factor delivery systems containing extracellular matrix components and the latest research progress regarding their application in the treatment of bone defects. METHODS: The first authors searched PubMed, Web of Science, Medline, Wanfang and CNKI databases to retrieve articles published during 2007-2019 with the search terms “extracellular matrix, integrins, heparin, heparin, growth factor, controlled delivery system, bone defect” in English and Chinese, respectively. A total of 317 articles were initially retrieved, and 59 of them were included in the final analysis. RESULTS AND CONCLUSION: Extracellular matrix components can combine and regulate the activity of growth factors and improve their bioavailability. Therefore, improvement of growth factor delivery system can be achieved by integrating extracellular matrix components into the growth factor delivery system. Compared with the common growth factor delivery system, the extracellular matrix growth factor delivery system can obtain better growth factor binding effect, higher biological activity and utilization, and even better targeted release, thus producing better effects on promoting bone regeneration. Therefore, the extracellular matrix growth factor delivery system provides a better therapeutic strategy for local treatment of refractory bone defects.
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Objective: To prepare the Lonicerae Japonicae Flos (LJF) extract supramolecular hydrogel and investigate its properties and release behavior in vitro. Methods: The LJF was extracted with 40% ethanol. Taking the content of phenolic acids as the quantitative index, N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine was selected as the gelator to prepare LJF extract supramolecular hydrogels. The release behavior was studied by in vitro release experiment. Results: The addition of LJF extract not only did not affect the formation of supramolecular hydrogel, but also improved the stability of supramolecular hydrogel. The release behavior of LJF extract was related to its loading and pH value of release medium. When the drug loading of LJF extract was 0.5 mg/mL, the cumulative release rate was the highest. Moreover, the cumulative release rate increased with the pH value of the release medium, showing obvious controlled release characteristics. Conclusion: Supramolecular hydrogels as the release carrier for LJF extract have an obvious sustained and controlled release, which provides a new idea for the development and application of LJF in medicine.
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ObjectiveTo prepare paclitaxel-loaded nanoparticles (NPs),and to observe drug biodistribution after intravascular infusion of the NPs using a DispatchTM catheter into New Zealand rabbit abdominal aorta models.Methods Paclitaxel-loaded NPs were prepared by ultrasonication/emulsificcation/solvent evaporation technique using biodegradable poly (lactic-co-glycolic acid)(PLGA) as drug carrier.NP size and morphology was assessed by submicro-laser defractometer and scanning electron microscopy.In vitro release of paclitaxel from the NPs was performed by shaking in PBS at 37℃.The NPs was delivered into New Zealand rabbit abdominal aorta using a DispatchTM catheter.ResultsThe diameter of paclitaxel NPs was around 246 nm with very narrow size distribution.The NPs showed good spherical shape with smooth uniform surface.Paclitaxel loading in the NPs was about 19.06％ with encapsulation efficiency about 93.25％.The NPs maintained a sustained in vitro drug release for 30 days in PBS.After in vivo NP infusion,paclitaxel was detected in the vascular tissue around the infusion site and it retained in the site for 21 days.ConclusionPLGA nanoparticles as local drug delivery carrier showed great potential to maintain a high local drug concentration and prolonged drug resident time in animal model in vivo.
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The treatments of infected bone defects are still a major clinical problem.In recent years,local delivery systems applied as anti-infection and bone repair material become a hot research topic.In this review,we discuss various influence factors such as osteoinductive growth factors,antibiotics,cartier material,extended release methods.We also introduce the recent progress in the development of local delivery system for the treatment of infected bone defects.
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The aim of the present work was to develop drug delivery system for localized controlled release of metronidazole following insertion into and/or around the periodontal pocket. This would ensure increased local drug concentration at the periodontal site to maintain an effective concentration over an extended period of time and a decrease in superfluous distribution of the drug to other body organs with a subsequent decrease in side effects. In the present work, metronidazole loaded chitosan microspheres were prepared by external gelation technique using tripolyphosphate as the cross-linker. The drug to polymer ratio was chosen at three levels: 1:4, 1:5 and 1:6 (by weight) and tripolyphosphate concentration also at three levels: 6, 12 and 18 (%). The microspheres were characterized for surface morphology, particle size, drug entrapment efficiency, swelling, erosion, bioadhesion and drug release profile. Nearly spherical, rough and porous particles (size ~ 800 μm) were obtained. Drug entrapment efficiency was found to be in the range of 60-75%. Percentage swelling, erosion and bioadhesion ranged from 10-25%, 5-15% and 43-59% respectively. The results indicated that formulation of metronidazole in chitosan microspheres could be utilized as a potential drug delivery system to periodontal pocket.
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Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor b1(TGF-beta1) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-beta type II receptor fused to the human immunoglobulin Fc portion (AdT beta-ExR) inhibits the action of TGF-beta probably either by adsorbing TGF-beta or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdT beta-ExR or adenovirus expressing b-galactosidase (AdCALacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RTPCR) were used for detection of type II TGF-beta receptor and its mRNA respectively. X-Gal histochemistry was performed to identify b-galactosidase. Both soluble TGF-beta receptor and b-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdT beta-ExR of 5x10(8) pfu and AdCALacZ of 2.5 x 10(8) pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-beta type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-beta signal pathway without any significant systemic side effect.
Subject(s)
Animals , Female , Adenoviridae/genetics , Catheters, Indwelling , Coronary Vessels/metabolism , Gene Expression , Genetic Therapy/adverse effects , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Inflammation/etiology , Receptors, Transforming Growth Factor beta/analysis , Swine , Transgenes , beta-Galactosidase/geneticsABSTRACT
Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor b1(TGF-beta1) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-beta type II receptor fused to the human immunoglobulin Fc portion (AdT beta-ExR) inhibits the action of TGF-beta probably either by adsorbing TGF-beta or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdT beta-ExR or adenovirus expressing b-galactosidase (AdCALacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RTPCR) were used for detection of type II TGF-beta receptor and its mRNA respectively. X-Gal histochemistry was performed to identify b-galactosidase. Both soluble TGF-beta receptor and b-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdT beta-ExR of 5x10(8) pfu and AdCALacZ of 2.5 x 10(8) pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-beta type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-beta signal pathway without any significant systemic side effect.
Subject(s)
Animals , Female , Adenoviridae/genetics , Catheters, Indwelling , Coronary Vessels/metabolism , Gene Expression , Genetic Therapy/adverse effects , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Inflammation/etiology , Receptors, Transforming Growth Factor beta/analysis , Swine , Transgenes , beta-Galactosidase/geneticsABSTRACT
BACKGROUND AND OBJECTIVES: Mechanisms of restenosis following successful coronary angioplasty (PTCA) are knownasvascularsmoothmuscle cells(VSMCs)proliferationandmigration, elastic recoil or vascular wall remodeling. Paclitaxel whose effect on the stabilization of microtubles leads to cell death is highly lipophilic, permitting easy pass through cell membrane, and has a long-term antiproliferative effect. This study was performed to evaluate effect of paclitaxel on VSMCs proliferation and whether locally delivered paclitaxel can prevent stenosis and neointimal formation in rat carotid artery injury model. MATERIALS AND METHODS: Cultured VSMCs were exposed to sequential concentrations of paclitaxel in vitro, and proliferation inhibition was analyzed with 3H-thymidine incorporation. Paclitaxel of a suitable concentration was applied to the endothelium-denuded carotid artery of Fisher 344 inbred rats for 20 minutes. Angiogram and morphometric analysis of carotid artery was performed after 2 weeks. RESULTS: 3H-thymidine incorporation in cultured VSMCs was decreased dose-dependently from the concentration of 0.1 micromol/L (2,454+/-149cpm/ microgram protein) to 100 micromol/L (1,323+/-69cpm/ microgram protein) of paclitaxel by single and 20-minute exposure in the presence of platelet-derived growth factor (p<0.005). In the absence of platelet-derived growth factor, the decrement of 3H-thymidine incorporation was evident above the concentration of 5 micromol/L of paclitaxel. To evaluate in vivo effect, paclitaxel (0.1 or 1 micromol/L) was administered into the endothelium-denuded carotid artery by balloon injury and incubated for 20 minutes. Percent stenoses (32.2+/-9.8%) of paclitaxel-treated group was less than those (46.3+/-7.5%) of control group on histologic analysis (p<0.01). Paclitaxel-treated group also had wider lumen on carotid angiogram and less neointimal thickening than control on histologic examination (p<0.005). CONCLUSION: Proliferation of VSMCs was effectively inhibited and neointimal formation and luminal stenosis was prevented in rat carotid artery injury model by single, brief and local delivery of low-dose paclitaxel. This strategy could be applied to clinical settings for the prevention of restenosis after PTCA.
Subject(s)
Animals , Rats , Angioplasty , Carotid Arteries , Carotid Artery Injuries , Cell Death , Cell Membrane , Constriction, Pathologic , Neointima , Paclitaxel , Phenobarbital , Platelet-Derived Growth FactorABSTRACT
Whether InfusaSleeve(IS) catheter can deliver antisense oligodeoxynucleotide (ODNs) following arterial denuation is unknown. We evaluate the feasibility of local endoluminal delivery of C-myc ODNs to the site of arterial denudation by using IS catheter and to determine the biological importance of these effects. IS catheter was introduced into right side of iliac artery of 21 rabbits after angioplasty of iliac artery. Animals were randomized to the control group (n＝6) receiving saline injection and the treated group receiving c-myc antisense (n＝15, 1 mg ODNs per vessel). In two weeks and 40 days following the operation, angiography was performed. Morphometric analyses were carried out in balloon-denuded iliac arteries. The expression of c-myc protein was detected by using a mouse monoclonal antibody to c-myc. Morphometric analyses carried out at 40 days after transcatheter c-myc antisense oligomer administration. The results showed that maximal neointimal area was reduced from 7.66±3.7(×105 μm2) in the control group (n＝6) to 4.04±1.02(×105 μm2) in the antisense treated group (n＝6, P＜0.05). These changes in vascular remodeling following denuding injury resulted in an increase in residual luman from 20～50% in the control group to 70～90% in the antisense-treated group. C-myc protein expression was virtually undetectable at baseline in locally ODNs-delivered arteries and detectable in control denuded arteries. The results show that: ①Single IS transcatheter administration allowed endoluminal delivery of ODNs to the site of arterial injury; ② c-myc antisense oligomer reduced the formation of neointime in denuded arteries, implying a therapeutic potential of this approach.
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OBJECTIVES:Coronary stent is one of the most effective currently available devices in the treatment of coronary artery diseases. But, coronary stent restenosis is one of major limitations in clinical stenting. Local drug delivery may be a new strategy for the prevention of stent restenosis. Endothelin receptor blocker is known to have vasodilatory and antiproliferative activities. To investigate the effects of local endothelin receptor blocker delivery on stent restenosis, local delivery was performed in the porcine model of coronary stent restenosis. METHODS: Stent overdilation injury alone was performed in the control porcine coronary arteries (n=4, group A) and local delivery of endothelin receptor blocker prior to stenting was performed in the porcine coronary artery (n=9, group B). Endothelin receptor blocker (TAK-044, Takeda, Japan) was delivered at a rate of 1 ml/min (50 mg/10 ml) using the Dispatch Catheter. Follow-up quantitative coronary angiogram (QCA) and immunohistopathologic assessment were performed 4 weeks after stenting. RESULTS: 1) On QCA, percent diameter stenosis was significantly higher in Group A than in Group B (29.4+/-6.1 % vs. 14.5+/-11.6%, p<0.05). 2) Area stenosis was higher in Group A than in Group B (63.5+/-23.2 % vs. 40.9+/-13.3 %) measured by histopathologic method (p<0.05). 3) Neointimal area was higher in Group A than in Group B (3.53+/-1.9 mm2 vs. 1.75+/-0.8 mm2, p=0.03). 4) By immunocytochemistry, proliferating cell nuclear antigen index was higher in Group A compared with Group B (46.8+/-5.2 % vs. 31.1+/-3.7 %, p<0.05). CONCLUSION: Local delivery of endothelin receptor blocker is effective in the prevention of stent restenosis in a porcine model, which may be related with the partial inhibition of cell proliferation of neointimal cells.
Subject(s)
Catheters , Cell Proliferation , Constriction, Pathologic , Coronary Artery Disease , Coronary Vessels , Endothelins , Follow-Up Studies , Immunohistochemistry , Proliferating Cell Nuclear Antigen , Receptors, Endothelin , StentsABSTRACT
BACKGROUND AND OBJECTIVES: Estrogen has been reported to inhibit migration and proliferation of vascular smooth muscle cells in vitro and in vivo. Sustained local delivery represents a potential alternative to systemic administrationbecauseitcan achieve higher tissue drug levels at site of balloon injury avoiding systemic side effects. We investigated the effect and mechanism of nanoparticulate sustained-release carrier system using liposome incorporating 17beta-estradiol (E2) on neointimal formation in rat carotid artery balloon injury model. MATERIALS AND METHODS: 17-estradiol benzoate, egg phosphatidylcholine, cholesterol, polyethyleneglycol-phosphatidylethanolamine were mixed to produce E2 -liposome formula where the final concentrations of lipids and E2 were 10 mg/ml and 66 M, respectively. The size of the particle was less than 200 nm. Rat carotid artery balloon injury model was used with Sprague-Dawley rats weighing 350+/-30g. Rats were divided into 3 groups of saline (n=22), liposome (n=46) and E2-liposome (n=46) and received 0.2 ml of each agent at injured site. 1) Rats from all groups were sacrificed at 7 (n=4), 14 (n=6), and 21 (n=12) days after injury, respectively. Morphometric analysis was performed for calculating medial area, neointimal area and I/M (intimal area/medialarea)ratio2)Rats from liposome and E2-liposome group sreceived 100mg/kg of 5-bromo-2'-deoxyuridine (BrdU) at 25, 9 and 1hr before sacrifice at 1 (n=4), 3 (n=4), 7 (n=4), and 14 (n=4) days after injury. BrdU and proliferating cell nuclear antigen (PCNA) stains were performed to elucidate a mechanism of inhibitory effect of E2. RESULTS: 1) There was no increase in the neointimal area in liposome group compared with saline group at 7, 14, and 21 days after injury, respectively. 2) There was 17%, 30%, and 34% reduction of I/M ratio in E2 -liposome group compared with liposome group at 7, 14 and 21 days after injury, respectively. 3) BrdU and PCNA stain revealed that at day 3, labelling index (LI) of media was lower in E2-liposome than in liposome group (p<0.05), and at day 7, LI of neointima was not significantly different between the two groups despite smaller neointimal area in the E2-liposomegroup. CONCLUSION: Nanoparticulateliposomeformula appears to be biocompatible. Local intraluminal infusion of E2 liposome formula after balloon injury of rat carotid artery significantly decreased neointimal formation. The mechanism seems to be the inhibitory effect on the proliferative response of smooth muscle cells in media at an early stage of injury. This formula appears to show potential for clinical applications in the prevention of neointimal formation following balloon angioplsty.
Subject(s)
Animals , Rats , Benzoates , Bromodeoxyuridine , Carotid Arteries , Cholesterol , Coloring Agents , Estrogens , Hyperplasia , Liposomes , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Neointima , Ovum , Phosphatidylcholines , Proliferating Cell Nuclear Antigen , Rats, Sprague-DawleyABSTRACT
20 Subjects with clinical diagnosis of adult periodontitis with sites having average pocket depth of 4mm were selected for the study. After scaling and root planing of those sites, 30% minocycline-HCl contained in biodegradable device were inserted in one group, scaling and root planing was carried out in another group and the last group was without any periodontal treatment. the difference between the groups was determined by pocket depth, bleeding on probing, attachment level, distribution of subgingival plaque bacteria. Conclusion was made for the comparisons between baseline and 4 weeks and the groups. 1. In analysis of pocket depth, there was significant difference in scaling and root planing group only. 2. Both the scaling and root planing group and minocycline group showed significant decrease in bleeding on probing. 3. There was significant increase in the attachment level in scaling and root planing group ,but no difference was foundbetween the groups. 4. There was significant decrease in the total number of subgingival bacteria in all groups and the number of motile bacteria decreased significantly in the minocycline group. These results indicate that insertion of Minocycline-HCl at the base of periodontal pocket was useful as an additional aid of mechanical treatment at the point of periodontal pocket, bleeding on probing, attachment level, microbial distribution.
Subject(s)
Adult , Humans , Bacteria , Chronic Periodontitis , Diagnosis , Hemorrhage , Minocycline , Periodontal Pocket , Root PlaningABSTRACT
BACKGROUND: The endovascular stent has been applied clinically in acute arterial occlusions after intimal dissection by angioplasty and in the prevention of restenosis. However, subacute stent thrombosis and restnosis remain major concerns in clinical stenting despite intravscular ultrasound guidance and high pressure inflation. Moreover, anticoagulation before and after stent implantation may be required for long periods and complicated by bleeding. A new strategy may be local drug delivery, which maintains sustained local concentration and may limit systemic complications. To evaluate the efficacy of local Nitric Oxide(NO) donor delivery on acute or subacute stent thrombosis and bleeding complications in patients, local NO donor delivery was performed in stented patients. METHOD: NO donor (2.0mg, Molsidomine) was delivered (1.0ml/min over 10min) using the Dispatch Catheter, after predilation of target lesion in 15 patients (8 angina, 7 myocardial infarction, mean age 5311.5 yr.) without heparin or nitrate infusion after stenting. After local NO donor delivery, Palmaz-Schatz stents were placed with standard methods. APTT and CK were checked at 1 hr, 3 hrs and 24 hrs after local NO donor delivery and STENTING. Follow-up coronary angiograms were done 48 hrs after stenting. RESULT: All patients had no hypotensive effects, no ischemic symptoms or no ECG changes during and after locaL NO donor delivery. ARTT and CK values were not changed at 3 and 24 hrs after local NO donor delivery and stenting. This allowed early arterial sheath removal. Follow-up coronary angiograms at 48 hrs showed all stents patent without stent recoil, with TIMI III flow, and without intra-stent thrombus. No target lesion revascularization and 100% event free survival were obsered for one month's clinical follow-up after NO donor delivery and stenting. Conclusion: Local NO donor delivery prior to stenting prevents acute and subacute stent thrombosis, systmic complications of nitrate, and maintains stent blood flow without stent recoil within the first one month after stenting.