"In Situ" Joint Preparation Technique for First Metatarsophalangeal Arthrodesis: A Retrospective Comparative Review of 388 Cases.

"Cup-shaped power reamers" and "flat cuts" (FC) are common joint preparation techniques in first metatarsophalangeal (MTP) joint arthrodesis. However, the third option of an "in situ" (IS) technique has rarely been studied. This study aims to compare the clinical, radiographic, and patient-reported outcomes (PROMs) of the IS technique for various MTP pathologies with other MTP joint preparation techniques. A single-center retrospective review was performed for patients who underwent primary MTP joint arthrodesis between 2015 and 2019. In total, 388 cases were included in the study. We found higher nonunion rates in the IS group (11.1% vs 4.6%, p = .016). However, the revision rates were similar between the groups (7.1% vs 6.5%, p = .809). Multivariate analysis revealed that diabetes mellitus was associated with significantly higher overall complication rates (p < .001). The FC technique was associated with transfer metatarsalgia (p = .015) and a more first ray shortening (p < .001). Visual analog scale, PROMIS-10 physical, and PROMIS-CAT physical scores significantly improved in IS and FC groups (p < .001, p = .002, p = .001, respectively). The improvement was comparable between the joint preparation techniques (p = .806). In conclusion, the IS joint preparation technique is simple and effective for first MTP joint arthrodesis. In our series, the IS technique had a higher radiographic nonunion rate that did not correlate with a higher revision rate, and otherwise similar complication profile to the FC technique while providing similar PROMs. The IS technique resulted in significantly less first ray shortening when compared to the FC technique.

High complication rates following revision first metatarsophalangeal joint arthrodesis: a retrospective analysis of 79 cases.

BACKGROUND: The most common indications for revision of first metatarsophalangeal joint (MTPJ) arthrodesis are symptomatic failures of prior arthrodesis, failed hallux valgus correction, and failed MTPJ arthroplasty implants. However, the outcomes of revision MTPJ arthrodesis have rarely been studied. The purpose of this study was to compare the clinical, radiographic, and patient-reported outcomes of revision MTPJ arthrodesis following different primary procedures. METHODS: A retrospective review of revision MTPJ arthrodesis cases between January 2015 and December 2019 was performed. The radiographic results, patient-reported outcomes, and rates of complications, subsequent revisions, and nonunions, were analyzed and compared preoperatively and postoperatively. A multivariate analysis was utilized to determine risk factors for complications and reoperations. RESULTS: This study yielded a total of 79 cases of revision MTPJ arthrodesis. The mean follow-up time was 365 days (SD ± 295). The overall complication rate was 40.5%, of which the overall nonunion rate was 19.0%. Seven cases (8.9%) required further revision surgery. The multivariate analysis revealed that Diabetes mellitus was associated with significantly higher overall complication rates (p = 0.016), and nonunion was associated with "in-situ" joint preparation techniques (p = 0.042). Visual Analog Scale (VAS) significantly improved postoperatively (p < 0.001); However, PROMIS-10 physical health and PROMIS-10 mental health did not change significantly during the study period. CONCLUSION: Treatment of MTPJ surgery failures is a clinical challenge in orthopedic surgery. In our study, revision of first MTPJ surgery resulted in higher nonunion rates and overall complication rates compared to typical outcomes from primary MTPJ arthrodesis. Diabetes, Tobacco use, and "in-situ" joint preparation technique were found to be independent risk factors for complications and reoperations. LEVEL OF EVIDENCE: III-Retrospective Cohort Study.

Calcium phosphate cement and locked plate augmentation of distal femoral defects: A biomechanical analysis.

PURPOSE: Bone tumors are common in the distal femur and often treated with intralesional curettage. The optimal method of stabilization of large distal femoral defects after curettage remains unclear. The goal of this study is to compare stabilization techniques for large distal femoral defects. METHODS: Large defects (60 cm3) were milled in the distal lateral metaphysis of 45 adult composite sawbone femurs. The defect was either (1) left untreated or reconstructed with (2) locked plate fixation, (3) calcium phosphate cement packing, or (4) locked plate fixation with calcium phosphate cement packing, or (5) polymethylmethacrylate packing. Each specimen then underwent axial and torsional stiffness testing followed by torsional loading to failure. The data were analyzed using ANOVA with Tukey-Kramer post-hoc analysis. RESULTS: The calcium phosphate cement filled defect with a locked plate was the stiffest construct in axial and torsional loading as well as the strongest in torque to failure. However, this difference only reached significance with respect to all other groups in torque to failure testing. The calcium phosphate cement filled defect with a locked plate was significantly stiffer than three of the four other groups in both axial and torsional stiffness testing. CONCLUSIONS: These results indicate that calcium phosphate cement, with or without the addition of locked plate fixation, may provide improved construct stability under time zero testing conditions. This result warrants further testing under cyclic loading condition and consideration for fixation of large femoral metaphyseal defects in future clincal trails.

Periprosthetic bacterial biofilm and quorum sensing.

Periprosthetic joint infection (PJI) is a common complication after total joint arthroplasty leading to severe morbidity and mortality. With an aging population and increasing prevalence of total joint replacement procedures, the burden of PJI will be felt not only by individual patients, but in increased healthcare costs. Current treatment of PJI is inadequate resulting in incredibly high failure rates. This is believed to be largely mediated by the presence of bacterial biofilms. These polymicrobial bacterial colonies form within secreted extracellular matrices, adhering to the implant surface and local tissue. The biofilm architecture is believed to play a complex and critical role in a variety of bacterial processes including nutrient supplementation, metabolism, waste management, and antibiotic and immune resistance. The establishment of these biofilms relies heavily on the quorum sensing communication systems utilized by bacteria. Early stage research into disrupting bacterial communication by targeting quorum sensing show promise for future clinical applications. However, prevention of the biofilm formation via early forced induction of the biofilm forming process remains yet unexplored. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2331-2339, 2018.

Polymeric nanoparticle drug delivery technologies for oral delivery applications.

INTRODUCTION: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery. AREAS COVERED: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations. EXPERT OPINION: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice.

Polymeric nanoparticle technologies for oral drug delivery.

Biologics increasingly are being used for the treatment of many diseases. These treatments typically require repeated doses administered by injection. Alternate routes of administration, particularly oral, are considered favorable because of improved convenience and compliance by patients, but physiological barriers such as extreme pH level, enzyme degradation, and poor intestinal epithelium permeability limit absorption. Encapsulating biologics in drug delivery systems such as polymeric nanoparticles prevents inactivation and degradation caused by low pH and enzymes of the gastrointestinal tract. However, transport across the intestinal epithelium remains the most critical barrier to overcome for efficient oral delivery. This review focuses on recent advances in polymeric nanoparticles being developed to overcome transport barriers and their potential for translation into clinical use.

Microfluidic platform for combinatorial synthesis and optimization of targeted nanoparticles for cancer therapy.

Taking a nanoparticle (NP) from discovery to clinical translation has been slow compared to small molecules, in part by the lack of systems that enable their precise engineering and rapid optimization. In this work we have developed a microfluidic platform for the rapid, combinatorial synthesis and optimization of NPs. The system takes in a number of NP precursors from which a library of NPs with varying size, surface charge, target ligand density, and drug load is produced in a reproducible manner. We rapidly synthesized 45 different formulations of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs of different size and surface composition and screened and ranked the NPs for their ability to evade macrophage uptake in vitro. Comparison of the results to pharmacokinetic studies in vivo in mice revealed a correlation between in vitro screen and in vivo behavior. Next, we selected NP synthesis parameters that resulted in longer blood half-life and used the microfluidic platform to synthesize targeted NPs with varying targeting ligand density (using a model targeting ligand against cancer cells). We screened NPs in vitro against prostate cancer cells as well as macrophages, identifying one formulation that exhibited high uptake by cancer cells yet similar macrophage uptake compared to nontargeted NPs. In vivo, the selected targeted NPs showed a 3.5-fold increase in tumor accumulation in mice compared to nontargeted NPs. The developed microfluidic platform in this work represents a tool that could potentially accelerate the discovery and clinical translation of NPs.

Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery.

Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are efficiently transported across the intestinal epithelium using both in vitro and in vivo models. In mice, orally administered FcRn-targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13.7%*hour compared with only 1.2%*hour for nontargeted nanoparticles. In addition, targeted nanoparticles containing insulin as a model nanoparticle-based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating that the enhanced nanoparticle transport was specifically due to FcRn. FcRn-targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration.

Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug.

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.

Nanoparticle encapsulation of mitaplatin and the effect thereof on in vivo properties.

Nanoparticle (NP) therapeutics have the potential to significantly alter the in vivo biological properties of the pharmaceutically active agents that they carry. Here we describe the development of a polymeric NP, termed M-NP, comprising poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-PEG), stabilized with poly(vinyl alcohol) (PVA), and loaded with a water-soluble platinum(IV) [Pt(IV)] prodrug, mitaplatin. Mitaplatin, c,c,t-[PtCl2(NH3)2(OOCCHCl2)2], is a compound designed to release cisplatin, an anticancer drug in widespread clinical use, and the orphan drug dichloroacetate following chemical reduction. An optimized preparation of M-NP by double emulsion and its physical characterization are reported, and the influence of encapsulation on the properties of the platinum agent is evaluated in vivo. Encapsulation increases the circulation time of Pt in the bloodstream of rats. The biodistribution of Pt in mice is also affected by nanoparticle encapsulation, resulting in reduced accumulation in the kidneys. Finally, the efficacy of both free mitaplatin and M-NP, measured by tumor growth inhibition in a mouse xenograft model of triple-negative breast cancer, reveals that controlled release of mitaplatin over time from the nanoparticle treatment produces long-term efficacy comparable to that of free mitaplatin, which might limit toxic side effects.

Synergistic cytotoxicity of irinotecan and cisplatin in dual-drug targeted polymeric nanoparticles.

AIM: Two unexplored aspects for irinotecan and cisplatin (I&C) combination chemotherapy are: actively targeting both drugs to a specific diseased cell type, and delivering both drugs on the same vehicle to ensure their synchronized entry into the cell at a well-defined ratio. In this work, the authors report the use of targeted polymeric nanoparticles (NPs) to coencapsulate and deliver I&C to cancer cells expressing the prostate-specific membrane antigen. MATERIALS & METHODS: Targeted NPs were prepared in a single step by mixing four different precursors inside microfluidic devices. RESULTS: I&C were encapsulated in 55-nm NPs and showed an eightfold increase in internalization by prostate-specific membrane antigen-expressing LNCaP cells compared with nontargeted NPs. NPs coencapsulating both drugs exhibited strong synergism in LNCaP cells with a combination index of 0.2. CONCLUSION: The strategy of coencapsulating both I&C in a single NP targeted to a specific cell type could potentially be used to treat different types of cancer.

Nanoparticle technologies for cancer therapy.

Nanoparticles as drug delivery systems enable unique approaches for cancer treatment. Over the last two decades, a large number of nanoparticle delivery systems have been developed for cancer therapy, including organic and inorganic materials. Many liposomal, polymer-drug conjugates, and micellar formulations are part of the state of the art in the clinics, and an even greater number of nanoparticle platforms are currently in the preclinical stages of development. More recently developed nanoparticles are demonstrating the potential sophistication of these delivery systems by incorporating multifunctional capabilities and targeting strategies in an effort to increase the efficacy of these systems against the most difficult cancer challenges, including drug resistance and metastatic disease. In this chapter, we will review the available preclinical and clinical nanoparticle technology platforms and their impact for cancer therapy.

Biodegradable, polymeric nanoparticle delivery systems for cancer therapy.

Nanotechnology has the potential to impact the treatment of cancer significantly. This review will explore how this potential is beginning to be realized through the design of polymeric nanoparticle delivery systems. Current research is focused on developing biocompatible nanoparticles capable of targeting specific cancer markers and delivering imaging and therapeutic agents for the detection and treatment of cancer, resulting in a number of preclinical and clinical applications. More sophisticated nanoparticle designs are now in development, including particles able to release multiple drugs for enhanced treatment efficacy and targeted, multifunctional particles capable of combining imaging and drug release.

Decreased protein expression and intermittent recoveries in BiP levels result from cellular stress during heterologous protein expression in Saccharomyces cerevisiae.

Cells are inherently robust to environmental perturbations and have evolved to recover readily from short-term exposure to heat, pH changes, and nutrient deprivation during times of stress. The stress of unfolded protein accumulation has been implicated previously in low protein yields during heterologous protein expression. Here we describe the dynamics of the response to this stress, termed the unfolded protein response (UPR), during the expression of the single chain antibody 4-4-20 (scFv) in Saccharomyces cerevisiae. Expression of scFv decreased the growth rate of yeast cells whether the scFv was expressed from single-copy plasmids or integrated into the chromosome. However, the growth rates recovered at longer expression times, and surprisingly, the recovery occurred more quickly in the high-copy integration strains. The presence of a functional UPR pathway was necessary for a recovery of normal growth rates. During the growth inhibition, the UPR pathway appeared to be activated, resulting in decreased intracellular scFv levels and intermittent recovery of the chaperone BiP within the endoplasmic reticulum. Intracellular scFv was observed primarily in the endoplasmic reticulum, consistent with activation of the UPR pathway. Although the intracellular scFv levels dropped over the course of the expression, this was not a result of scFv secretion. A functional UPR pathway was necessary for the drop in intracellular scFv, suggesting that the decrease was a direct response of UPR activation. Taken together, these results suggest that control of heterologous gene expression to avoid UPR activation will result in higher production levels.