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Bioactive Materials Sep 2023Currently, many cancer patients with bone defects are still threatened by tumor recurrence, postoperative bacterial infection, and massive bone loss. Many methods have...
Currently, many cancer patients with bone defects are still threatened by tumor recurrence, postoperative bacterial infection, and massive bone loss. Many methods have been studied to endow bone implants with biocompatibility, but it is difficult to find an implant material that can simultaneously solve the problems of anticancer, antibacterial and bone promotion. Here, a multifunctional gelatin methacrylate/dopamine methacrylate adhesive hydrogel coating containing 2D black phosphorus (BP) nanoparticle protected by polydopamine (pBP) is prepared by photocrosslinking to modify the surface of poly (aryl ether nitrile ketone) containing phthalazinone (PPENK) implant. The multifunctional hydrogel coating works in conjunction with pBP, which can deliver drug through photothermal mediation and kill bacteria through photodynamic therapy at the initial phase followed by promotion of osteointegration. In this design, photothermal effect of pBP control the release of doxorubicin hydrochloride loaded via electrostatic attraction. Meanwhile, pBP can generate reactive oxygen species (ROS) to eliminate bacterial infection under 808 nm laser. In the slow degradation process, pBP not only effectively consumes excess ROS and avoid apoptosis induced by ROS in normal cells, but also degrade into PO to promote osteogenesis. In summary, nanocomposite hydrogel coatings provide a promising strategy for treatment of cancer patients with bone defects.
PubMed: 37397628
DOI: 10.1016/j.bioactmat.2023.04.020 -
Pharmaceutics Nov 2023The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention...
The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0-2.5], 1.9 [1.2-6.3] and 2.8 [2.3-11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229-1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model.
PubMed: 38140017
DOI: 10.3390/pharmaceutics15122676 -
International Journal of Pharmaceutics Jul 2023Perseris is asubcutaneous extended-release risperidone in situ forming implant (suspension) indicated for the treatment of adult schizophrenia. Owing to the release rate...
Perseris is asubcutaneous extended-release risperidone in situ forming implant (suspension) indicated for the treatment of adult schizophrenia. Owing to the release rate controlling polymer poly(lactide-co-glycolide) (PLGA), one injection of Perseris can deliver risperidone for one month, which significantly reduces the administration frequency and improves patient compliance. The PLGA and drug used in Perseris was previously identified through reverse engineering and two compositionally equivalent formulations (F-1 and F-2) showing similar in vitro drug release were developed. The current work focuses on in vivo exploration of Perseris and the developed compositionally equivalent formulations using a rabbit model and further evaluate the sameness of the developed formulations compared to Perseris. The in vivo pharmacokinetic (PK) profiles, drug absorption rate, phase separation rate, macro appearance, weight loss as well as the water uptake of the solidified drug depots at different time points were investigated and compared with the in vitro release data as well as with dog and human in vivo data available in literature. Results show that the rabbit PK profile of Perseris was relevant with those obtained from both the dog model and the clinical data, indicating that the rabbit model is appropriate for investigation of the in vivo performance of risperidone implants. Consistent with their similar in vitro drug release, the two compositionally equivalent formulations demonstrated similar PK profiles, drug absorption rates, weight loss and swelling in vivo compared to Perseris. Although the erosion mechanism appeared to be similar between in vitro and in vivo, there were in vitro-in vivo differences concerning the drug release kinetics, phase separation rates and swelling behavior. This work provides a comprehensive in vitro/in vivo understanding of Perseris and the developed compositionally equivalent formulations, which will be beneficial for future development of generic as well as novel PLGA in situ forming implant products.
Topics: Humans; Animals; Rabbits; Dogs; Risperidone; Polylactic Acid-Polyglycolic Acid Copolymer; Drug Carriers; Drug Compounding; Drug Liberation; Microspheres
PubMed: 37354927
DOI: 10.1016/j.ijpharm.2023.123170 -
Journal of Controlled Release :... Sep 2023Despite the unique advantages of injectable, long-acting in situ forming implant formulations based on poly(lactide-co-glycolide) (PLGA) and N-Methyl-2-Pyrrolidone...
Despite the unique advantages of injectable, long-acting in situ forming implant formulations based on poly(lactide-co-glycolide) (PLGA) and N-Methyl-2-Pyrrolidone (NMP), only six products are commercially available. A better understanding of PLGA will aid in the development of more in situ forming implant innovator and generic products. This article investigates the impact of slight changes in PLGA attributes, i.e., molecular weight (MW), lactide:glycolide (L/G) ratio, blockiness, and end group, on the in vitro and in vivo performance of PLGA-based in situ forming implant formulations. Perseris (risperidone) for extended-release injectable suspension was selected as the reference listed drug (RLD). A previously developed adapter-based USP 2 method was used for the in vitro release testing of various risperidone implant formulations. A rabbit model was used to determine the in vivo pharmacokinetic profiles of the formulations (subcutaneous administration) and deconvolution (Loo-Riegelman method) was conducted to obtain the in vivo release profiles. The results showed that a 5 KDa difference in the MW (19.2, 24.2, 29.2 KDa), a 5% variation in the L/G ratio (85/15, 80/20, 75/25) and the end-cap (acid vs ester) all significantly impacted the formulation behavior both in vitro and in vivo. Higher MW, higher L/G ratio and ester end-cap PLGA all resulted in longer release durations. The formulations prepared with polymers with different blockiness values (within the blockiness range tested) did not show differences in in vitro and in vivo release. An in vitro-in vivo correlation (IVIVC) was not developed due to the different in vitro and in vivo phase separation rates, swelling tendencies and consequent significantly different release profiles. This is the first report evaluating the impact of PLGA property variation (over a narrow range) on the performance of in situ forming implants. The knowledge gained will provide a better understanding of the mechanisms underlying risperidone in situ forming implant performance and will aid the development of future products.
Topics: Animals; Rabbits; Risperidone; Esters; Molecular Weight; Oligonucleotides; Polymers
PubMed: 37591464
DOI: 10.1016/j.jconrel.2023.08.029 -
Journal of Nanobiotechnology Aug 2023Implant infections caused by biofilm forming bacteria are a major threat in orthopedic surgery. Delivering antibiotics directly to an implant affected by a bacterial...
BACKGROUND
Implant infections caused by biofilm forming bacteria are a major threat in orthopedic surgery. Delivering antibiotics directly to an implant affected by a bacterial biofilm via superparamagnetic nanoporous silica nanoparticles could present a promising approach. Nevertheless, short blood circulation half-life because of rapid interactions of nanoparticles with the host's immune system hinder them from being clinically used. The aim of this study was to determine the temporal in vivo resolution of magnetic nanoporous silica nanoparticle (MNPSNP) distribution and the effect of PEGylation and clodronate application using PET/CT imaging and gamma counting in an implant mouse model.
METHODS
PEGylated and non-PEGylated MNPSNPs were radiolabeled with gallium-68 (Ga), implementing the chelator tris(hydroxypyridinone). 36 mice were included in the study, 24 mice received a magnetic implant subcutaneously on the left and a titanium implant on the right hind leg. MNPSNP pharmacokinetics and implant accumulation was analyzed in dependence on PEGylation and additional clodronate application. Subsequently gamma counting was performed for further final analysis.
RESULTS
The pharmacokinetics and biodistribution of all radiolabeled nanoparticles could clearly be visualized and followed by dynamic PET/CT imaging. Both variants of Ga-labeled MNPSNP accumulated mainly in liver and spleen. PEGylation of the nanoparticles already resulted in lower liver uptakes. Combination with macrophage depletion led to a highly significant effect whereas macrophage depletion alone could not reveal significant differences. Although MNPSNP accumulation around implants was low in comparison to the inner organs in PET/CT imaging, gamma counting displayed a significantly higher %I.D./g for the tissue surrounding the magnetic implants compared to the titanium control. Additional PEGylation and/or macrophage depletion revealed no significant differences regarding nanoparticle accumulation at the implantation site.
CONCLUSION
Tracking of Ga-labeled nanoparticles in a mouse model in the first critical hours post-injection by PET/CT imaging provided a better understanding of MNPSNP distribution, elimination and accumulation. Although PEGylation increases circulation time, nanoparticle accumulation at the implantation site was still insufficient for infection treatment and additional efforts are needed to increase local accumulation.
Topics: Animals; Mice; Positron Emission Tomography Computed Tomography; Clodronic Acid; Gallium Radioisotopes; Nanopores; Tissue Distribution; Titanium; Disease Models, Animal; Magnetic Phenomena
PubMed: 37592318
DOI: 10.1186/s12951-023-02041-8 -
Advanced Healthcare Materials May 2024Hydrogels are well-suited for biomedical applications due to their numerous advantages, such as excellent bioactivity, versatile physical and chemical properties, and... (Review)
Review
Hydrogels are well-suited for biomedical applications due to their numerous advantages, such as excellent bioactivity, versatile physical and chemical properties, and effective drug delivery capabilities. Recently, hydrogel coatings have developed to functionalize bone implants which are biologically inert and cannot withstand the complex bone tissue repair microenvironment. These coatings have shown promise in addressing unique and pressing medical needs. This review begins with the major functionalized performance and interfacial bonding strategy of hydrogel coatings, with a focus on the novel external field response properties of the hydrogel. Recent advances in the fabrication strategies of hydrogel coatings and their use in the treatment of pathologic bone regeneration are highlighted. Finally, challenges and emerging trends in the evolution and application of physiological environment-responsive and external electric field-responsive hydrogel coatings for bone implants are discussed.
PubMed: 38794971
DOI: 10.1002/adhm.202401296 -
Drug Delivery and Translational Research Nov 2023Besides enhancing osseo- and soft tissue integration, modulating inflammation at the implant site is also crucial for dental implant success. Uncontrolled peri-implant...
Besides enhancing osseo- and soft tissue integration, modulating inflammation at the implant site is also crucial for dental implant success. Uncontrolled peri-implant inflammation can cause significant loss of surrounding tissue and implant failure. It was recently shown that microvesicles (MVs), a less-studied type of extracellular vesicles, play a crucial role in cell-to-cell communication and may modulate angiogenesis and inflammatory response. The effect of MVs on regulating inflammation at an implant site, however, remains unexplored. In the current study, MVs were isolated and characterised from human primary gingival fibroblasts (hGFs) and loaded within titania nanotubes (TNTs, fabricated via anodisation on 3D Ti wire implants) towards their local release. The modified implants were characterised using SEM and confocal imaging to confirm the loading and local release of MVs from TNTs. In vitro studies demonstrated the internalisation of hGFs-MVs by human gingival keratinocytes (OKF6/TERT2 cell line), which caused a significant reduction in the production of pro-inflammatory cytokines. The results support MVs-releasing TNTs as a promising implant surface modification strategy to reduce inflammation, paving the way for further advancements in therapeutic dental implants.
PubMed: 37985540
DOI: 10.1007/s13346-023-01457-x -
Calcified Tissue International Sep 2023Together with diabetic osteoporosis (DOP), diabetes patients experience poor peri-implant osteogenesis following implantation for dentition defects. Zoledronate (ZOL) is...
Together with diabetic osteoporosis (DOP), diabetes patients experience poor peri-implant osteogenesis following implantation for dentition defects. Zoledronate (ZOL) is widely used to treat osteoporosis clinically. To evaluate the mechanism of ZOL for the treatment of DOP, experiments with DOP rats and high glucose-grown MC3T3-E1 cells were used. The DOP rats treated with ZOL and/or ZOL implants underwent a 4-week implant-healing interval, and then microcomputed tomography, biomechanical testing, and immunohistochemical staining were performed to elucidate the mechanism. In addition, MC3T3-E1 cells were maintained in an osteogenic medium with or without ZOL to confirm the mechanism. The cell migration, cellular actin content, and osteogenic differentiation were evaluated by a cell activity assay, a cell migration assay, as well as alkaline phosphatase, alizarin red S, and immunofluorescence staining. The mRNA and protein expression of adenosine monophosphate-activated protein kinase (AMPK), phosphorylated AMPK (p-AMPK), osteoprotegerin (OPG), receptor activator of nuclear factor kappa B ligand (RANKL), bone morphogenetic protein 2 (BMP2), and collagen type I (Col-I) were detected using real-time quantitative PCRs and western blot assays, respectively. In the DOP rats, ZOL markedly improved osteogenesis, enhanced bone strength and increased the expression of AMPK, p-AMPK, and Col-I in peri-implant bones. The in vitro findings showed that ZOL reversed the high glucose-induced inhibition of osteogenesis via the AMPK signaling pathway. In conclusion, the ability of ZOL to promote osteogenesis in DOP by targeting AMPK signaling suggests that therapy with ZOL, particularly simultaneous local and systemic administration, may be a unique approach for future implant repair in diabetes patients.
Topics: Rats; Animals; Zoledronic Acid; Osteogenesis; AMP-Activated Protein Kinases; X-Ray Microtomography; Osteoporosis; Cell Differentiation; Glucose; Osteoblasts; Diabetes Mellitus
PubMed: 37392365
DOI: 10.1007/s00223-023-01112-0 -
Clinical Oral Implants Research Mar 2024To evaluate long-term outcomes and prognostic factors of non-reconstructive surgical treatment of peri-implantitis.
AIM
To evaluate long-term outcomes and prognostic factors of non-reconstructive surgical treatment of peri-implantitis.
MATERIALS AND METHODS
One hundred forty-nine patients (267 implants) were surgically treated for peri-implantitis and followed for an average of 7.0 (SD: 3.6) years. The primary outcome was implant loss. Additional bone loss and surgical retreatment were secondary outcomes. Patient/implant characteristics, as well as clinical and radiographic parameters collected prior to initial surgery, were evaluated as potential predictors of implant loss. Flexible parametric survival models using restricted cubic spline functions were used; 5- and 10-year predicted rates of implant loss were calculated according to different scenarios.
RESULTS
Fifty-three implants (19.9%) in 35 patients (23.5%) were lost during the observation period. Implant loss occurred after a mean period of 4.4 (SD: 3.0) years and was predicted by implant surface characteristics (modified surface; HR 4.5), implant length (HR 0.8 by mm), suppuration at baseline (HR 2.7) and disease severity (baseline bone loss: HR 1.2 by mm). Estimates of 5- and 10-year implant loss ranged from 1% (best prognostic scenario; initial bone loss <40% of implant length, turned implant surface and absence of suppuration on probing (SoP)) to 63% (worst prognostic scenario; initial bone loss ≥60% of implant length, modified implant surface and SoP) and from 3% to 89%, respectively. Surgical retreatment was performed at 65 implants (24.3%) in 36 patients (24.2%) after a mean time period of 4.5 (3.1) years. In all, 59.5% of implants showed additional bone loss, were surgically retreated or lost.
CONCLUSIONS
Recurrence of disease is common following surgical treatment of peri-implantitis. The strongest predictor for implant loss was implant surface characteristics. Implant length as well as suppuration and disease severity at baseline were also relevant factors.
Topics: Humans; Peri-Implantitis; Retrospective Studies; Prognosis; Alveolar Bone Loss; Suppuration; Dental Implants
PubMed: 38112108
DOI: 10.1111/clr.14228 -
Plastic and Reconstructive Surgery Sep 2023The Ideal Implant structured breast implant uses different technology than unstructured saline or silicone gel implants, making it a third type of implant. U.S. Food and...
BACKGROUND
The Ideal Implant structured breast implant uses different technology than unstructured saline or silicone gel implants, making it a third type of implant. U.S. Food and Drug Administration (FDA) and Health Canada granted approval in November of 2014. This saline-filled implant has an internal structure consisting of a series of nested shells that support the upper pole when upright and control movement of the saline to provide a natural feel. Because women can look in the mirror to know their implants are intact, they have peace of mind. In contrast, most women are concerned about silicone gel implant ruptures, which are silent and require FDA-recommended magnetic resonance imaging or ultrasound scans for detection.
METHODS
This U.S. trial enrolled 502 women: 399 for primary and 103 for revision augmentation. Investigators were 45 American Board of Plastic Surgery-certified plastic surgeons at 35 sites. Of the 502 women enrolled, 426 (84.9%) completed 10-year follow-up visits, a higher percentage than all other FDA breast implant trials.
RESULTS
Through 10 years of follow-up, surgeon satisfaction was 94.8% for primary and 87.4% for revision augmentation; and patient satisfaction was 92.7% for primary and 82.3% for revision augmentation. Cumulative Kaplan-Meier risk rates for two major adverse events were lower than in the silicone gel implant trials: Baker class III and IV capsular contracture was 6.6% for primary and 11.5% for revision augmentation; and rupture/deflation was 3.7% for primary and 4.7% for revision augmentation.
CONCLUSION
Ten-year results from 426 women show the Ideal Implant has high patient and surgeon satisfaction, a low rate of capsular contracture, and a low rate of rupture/deflation.
CLINICAL QUESTION/LEVEL OF EVIDENCE
Therapeutic, IV.
Topics: Female; Humans; Breast Implants; Silicone Gels; Follow-Up Studies; Breast; Breast Implantation; Reoperation; Saline Solution; Contracture; Postoperative Complications; Implant Capsular Contracture; Prosthesis Design
PubMed: 36827477
DOI: 10.1097/PRS.0000000000010312