Combination Antibiotic Delivery in PMMA Provides Sustained Broad-Spectrum Antimicrobial Activity and Allows for Postimplantation Refilling.

Antibiotics are commonly added to poly(methyl methacrylate) (PMMA) by surgeons to locally treat infections such as in bone cement for joint replacement surgeries, as well as implantable antimicrobial "beads". However, this strategy is of limited value in high-risk patients where infections can be recurrent or chronic and otherwise hard to treat. Also, when only one drug is incorporated and applied toward polymicrobial infections (multiple bacterial species), there is a high risk that bacteria can develop antibiotic resistance. To combat these limitations, we developed a combination antibiotic PMMA composite system composed of rifampicin-filled ß-cyclodextrin (ß-CD) microparticles added into PMMA filled with a second drug. Different formulations were evaluated through zone of inhibition, drug activity, antibiotic release, and refilling, as well as mechanical studies. Our combination antibiotic PMMA composite system achieved up to an 8-fold increase in the duration of antimicrobial activity in comparison to clinically used antibiotic-filled PMMA. Inclusion of CD microparticles also allowed for refilling of additional antibiotics after simulated implantation, resulting in additional windows of therapeutic efficacy. Mechanical testing showed that our tested formulations did have a small, but significant decrease in mechanical properties when compared to unmodified controls. While further studies are needed to determine whether the tested formulations are still suitable for load-bearing applications (e.g., bone cement), our composites are certainly amenable for a variety of nonload-bearing applications (e.g., antimicrobial "beads" and temporary spacer in two-stage arthroscopic revisions).

Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes.

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.

Cyclodextrin Polymer Preserves Sirolimus Activity and Local Persistence for Antifibrotic Delivery over the Time Course of Wound Healing.

Fibrosis and dysphagic stricture of the esophagus is a major unaddressed problem often accompanying endoscopic removal of esophageal cancers and precancerous lesions. While weekly injections of antiproliferative agents show potential for improved healing, repeated injections are unlikely clinically and may alternatively be replaced by creating an esophageal drug delivery system. Affinity-based polymers have previously shown success for continuous delivery of small molecules for weeks to months. Herein, we explored the potential of an affinity-based microparticle to provide long-term release of an antiproliferative drug, sirolimus. In molecular docking simulations and surface plasmon resonance experiments, sirolimus was found to have suitable affinity for beta-cyclodextrin, while dextran, as a low affinity control, was validated. Polymerized beta-cyclodextrin microparticles exhibited 30 consecutive days of delivery of sirolimus during in vitro release studies. In total, the polymerized beta-cyclodextrin microparticles released 36.9 mg of sirolimus per milligram of polymer after one month of incubation in vitro. Taking daily drug release aliquots and applying them to PT-K75 porcine mucosal fibroblasts, we observed that cyclodextrin microparticle delivery preserved bioactivity of sirolimus inhibiting proliferation by 27-67% and migration of fibroblasts by 28-100% of buffer treated controls in vitro. Testing for esophageal injection site losses, no significant loss was incurred under simulated saliva flow for 10 min, and 16.7% of fluorescently labeled polymerized cyclodextrin microparticle signal was retained at 28 days after submucosal injection in esophageal tissue ex vivo versus only 4% of the initial amount remaining for free dye molecules injected alone. By combining affinity-based drug delivery for continuous long-term release with a microparticle platform that is injectable yet remains localized in tissue interstitium, this combination platform demonstrates promise for preventing esophageal fibrosis and stricture.

Current Options and Emerging Biomaterials for Periprosthetic Joint Infection.

PURPOSE OF REVIEW: Infection in the setting of total joint arthroplasty, referred to as periprosthetic joint infection (PJI), is a devastating complication requiring prolonged and costly treatment. The unique environment around an artificial joint and ability of surrounding tissues to sequester bacteria collectively make prevention, diagnosis, and treatment of this condition challenging. In light of the unique pathogenesis of PJI, this review explores the limitations of contemporary treatments and discusses novel treatment options. RECENT FINDINGS: Recent advancements in local antibiotic delivery platforms for preventing and treating PJI include titanium nanotube arrays, synthetic polymers, resorbable hydrogels, and cyclodextrin-based drug delivery options. In particular, cyclodextrins have facilitated great advancements in other clinical disorders and have demonstrated early promise as a future option in the arena of PJI. Novel treatment modalities for PJI optimize the implant surfaces to prevent bacterial biofilm formation or provide prolonged intra-articular antibiotic dosing to eradicate bacteria.

Pseudopolyrotaxane Formation in the Synthesis of Cyclodextrin Polymers: Effects on Drug Delivery, Mechanics, and Cell Compatibility.

Numerous groups have reported the use of cyclodextrin (CD)-based polymers for drug delivery applications due to their capacity to form inclusions with small molecule drugs, delaying the rate of drug release beyond that of diffusion alone (termed "affinity-based" drug delivery). Herein we demonstrate synthesis and characterization of a new family of CD-based polymers, some as pseudopolyrotaxanes, generated under mild (aqueous, room temperature) conditions. The formation of these new affinity polymers results in broad mechanical properties. Three diglycidylether cross-linkers which vary in length from 0 to 10 ethylene glycol units were examined. Pseudopolyrotaxane formation was found only with the highest-length cross-linker, noted first by a sharp change in both material properties and then confirmed by chemical signature. Materials were thoroughly evaluated by NMR, DSC, DMA, TGA, XRD, and FTIR. Cross-linker choice was also tested for impact on drug loading and delivery capacity, using antibiotics as model drugs. Chemically similar polymers without showing affinity rapidly saturated in loading experiments, while affinity materials showing high capacity for drug loading, even beyond the solubility limit of the drugs. When using the polymers with these new cross-linkers, affinity-based drug delivery is maintained: the materials are capable of antibiotic delivery, and clearance of Staphylococcus aureus, at least an order of magnitude better than diffusion-only control polymers. In cell compatibility studies, CD-based polymers were shown to have low overt cell toxicity and even resisted cell adhesion, presumably due to their highly hydrated state.

Using Affinity To Provide Long-Term Delivery of Antiangiogenic Drugs in Cancer Therapy.

Antiangiogenic drugs encompass many of the different cancer drugs currently under clinical investigation. One of the drawbacks of antiangiogenic therapy, though, is that upon cessation of drug treatment tumors can recur with an accelerated growth rate. In this study we investigate the capacity of using affinity interactions between a polymer made from cyclodextrin and four antiangiogenic drugs, tranilast, SU5416, 2-methoxyestradiol, and silibinin, with the ultimate goal of creating delivery profiles on the order of antiangiogenic processes (needing weeks, rather than hours of delivery). In these systems, release rate is dependent on affinity, so using in silico molecular docking studies followed by surface plasmon resonance we determined that silibinin possesses the highest affinity among the drugs screened. Silibinin also showed a differential binding affinity among various cyclodextrins tested, with a greater affinity toward the larger molecular pocket of γ-cyclodextrin than for ß-cyclodextrin. Release studies confirmed this affinity to translate into a slower, more sustained release of silibinin. Similarly we found this trend in the release of tranilast. Then using U87 human glioblastoma cells in a mouse xenograft model, we showed that affinity-based cyclodextrin polymers loaded with silibinin showed substantially longer release rates than nonaffinity control polymers; however, both were capable of inhibiting tumor growth in the time frame studied. From this work we showed three different, but chemically similar, polymers, each with a different release rate. Future work is on evaluating longer term tumor models where this longer release rate from affinity delivery systems might have additional advantages over polymers dependent only on diffusion.

Infection prevention using affinity polymer-coated, synthetic meshes in a pig hernia model.

BACKGROUND: Given concern for hernia mesh infection, surgeons often use biologic mesh which may provide reduced risk of infection but at the cost of decreased repair durability. We evaluated mesh coating to provide sustained release of antibiotics to prevent prosthetic mesh infection and also allow a durable repair. MATERIALS AND METHODS: Cyclodextrin-based polymer was crosslinked onto multifilament polyester mesh and loaded with vancomycin (1.75 mg/cm2). Pigs received modified meshes (n = 6) or normal, untreated meshes (n = 4), which were implanted into acute 10 × 5 cm ventral hernia, then directly inoculated with 106 colony-forming unit (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). These were compared to animals receiving normal, uninfected mesh. All mesh was secured in an underlay bridge manner, and after 30 d, the abdominal wall was removed for quantitative bacterial culture and biomechanical analysis. RESULTS: All animals survived 30 d. All six animals with coated mesh cleared MRSA infection. The four control animals did not clear MRSA (P = 0.005). Quantitative bacterial load was higher in standard mesh versus drug-delivery mesh group (2.34 × 104versus 80.9 CFU/gm). These data were log10-transformed and analyzed by Welch's t-test (P = 0.001). Minimum number of CFUs detectable by assay (300) was used instead of zero. Biomechanical analysis of controls (1.82 N/mm infected; 1.71 N/mm uninfected) showed no difference to the modified meshes (1.31 N/mm) in tissue integration (P = 0.15). CONCLUSIONS: We successfully prevented synthetic mesh infection in a pig model using a cyclodextrin-based polymer to locally deliver vancomycin to the hernia repair site and clearing antibiotic-resistant bacteria. Polymer coating did not impact the strength of the hernia repair.

Antibiotic-releasing microspheres prevent mesh infection in vivo.

BACKGROUND: Infection remains a dreaded complication after implantation of surgical prosthetics, particularly after hernia repair with synthetic mesh. We previously demonstrated the ability of a newly developed polymer to provide controlled release of an antibiotic in a linear fashion over 45 d. We subsequently showed that coating mesh with the drug-releasing polymer prevented a Staphylococcus aureus (SA) infection in vivo. To broaden the applicability of this technology, the polymer was synthesized as isolated "microspheres" and loaded with vancomycin (VM) before conducting a noninferiority analysis. MATERIALS AND METHODS: Seventy-three mice underwent creation of a dorsal subcutaneous pocket that was inoculated with 104 colony forming units (CFU) of green fluorescent protein (GFP)-labeled SA (105 CFU/mL). Multifilament polyester mesh (7 × 7 mm) was placed into the pocket, and the skin was closed. Mesh was either placed alone (n = 16), coated with VM-loaded polymer (n = 20), placed next to VM-loaded microspheres (n = 20) or unloaded microspheres (n = 10), or flushed with VM solution (n = 7). Quantitative tissue/mesh cultures were performed at 2 and 4 week. Mice with open wounds and explanted mesh were excluded. RESULTS: Twenty-two of 23 (96%) tissue-mesh samples from mesh alone or empty miscrospheres were positive for GFP-labeled SA at 2 and 4 wk. Six of seven (86%) samples from the VM flush group were positive for GFP SA at 4 wk. Thirty-eight of 38 (100%) VM-loaded crosslinked cyclodextrin polymers-coated mesh or VM-loaded microspheres were negative for GFP SA at 2 and 4 wk. CONCLUSIONS: Slow affinity-based drug-releasing polymers in the form of microspheres are able to adequately clear a bacterial burden of SA and prevent mesh infection.

The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration.

Chemotactic factors direct the migration of immune cells, multipotent stem cells, and progenitor cells under physiologic and pathologic conditions. Chemokine ligand 12 and chemokine ligand 7 have been identified and investigated in multiple studies for their role in cellular trafficking in the setting of tissue regeneration. Recent early phase clinical trials have suggested that these molecules may lead to clinical benefit in patients with chronic disease. Importantly, these two proteins may play additional significant roles in directing the migration of multipotent cells, such as mesenchymal stem cells and hematopoietic progenitor cells. This article reviews the functions of these two chemokines, focusing on recruitment to sites of injury, immune function modulation, and contributions to embryonic development. Additional research would provide valuable insight into the potential clinical application of these two proteins in stem cell therapy.

Polymerized cyclodextrin microparticles for sustained antibiotic delivery in lung infections.

Pulmonary infections complicate chronic lung diseases requiring attention to both the pathophysiology and complexity associated with infection management. Patients with cystic fibrosis (CF) struggle with continuous bouts of pulmonary infections, contributing to lung destruction and eventual mortality. Additionally, CF patients struggle with airways that are highly viscous, with accumulated mucus creating optimal environments for bacteria colonization. The unique physiology and altered airway environment provide an ideal niche for bacteria to change their phenotype often becoming resistant to current treatments. Colonization with multiple pathogens at the same time further complicate treatment algorithms, requiring drug combinations that can challenge CF patient tolerance to treatment. The goal of this research initiative was to explore the utilization of a microparticle antibiotic delivery system, which could provide localized and sustained antibiotic dosing. The outcome of this work demonstrates the feasibility of providing efficient localized delivery of antibiotics to manage infection using both preclinical in vitro and in vivo CF infection models. The studies outlined in this manuscript demonstrate the proof-of-concept and unique capacity of polymerized cyclodextrin microparticles to provide site-directed management of pulmonary infections.

Adjustable release of mitomycin C for inhibition of scar tissue formation after filtration surgery.

The aim of this study is to demonstrate a drug delivery system with the capacity to adjust the release of mitomycin C (MMC), based on polymer composition, and inhibit fibroblast proliferation to a better effect than is currently used in glaucoma filtration surgery. The polymer used in this work is made from the oligosaccharide cyclodextrin, from which others and we have demonstrated adjustable release of small molecule drugs due to specific molecular interactions or "affinity" between drug and the cyclodextrin polymer. To adjust release rate, cyclodextrin polymers were synthesized in either dimethylformamide (DMF) or dimethyl sulfoxide, (DMSO) at a crosslinking ratio of 1:0.16 or 1:0:32 (molecule of glucose: molecule of crosslinker). The polymers were then loaded with mitomycin C, dried, and release evaluated in a physiological environment. Drug release was determined by visible spectroscopy. Released aliquots of mitomycin C were incubated with 3T3 fibroblast cells to determine cytotoxic or inhibitory effect through a cell proliferation assay. We show that by using affinity between drug and polymer, we can adjust MMC release rates to be slower and more sustained than from conventional, diffusion-only polymers, for both the DMF polymers (p = 0.00526) and the DMSO polymers (p = 0.0113). The incorporated and released MMC maintains inhibition of fibroblast proliferation much longer than is possible with a one-time application. Affinity polymers with 1:0.16 and 1:0.32 crosslink ratio showed significant inhibition of proliferation for up to 100 h (p = 0.018 and p = 0.014 respectively). The use of our controlled drug delivery technology applied after surgery could have a greater therapeutic impact than the current one-time applications of MMC.

Using glycosaminoglycan/chemokine interactions for the long-term delivery of 5P12-RANTES in HIV prevention.

5P12-RANTES is a recently developed chemokine analogue that has shown high level protection from SHIV infection in macaques. However, the feasibility of using 5P12-RANTES as a long-term HIV prevention agent has not been explored partially due to the lack of available delivery devices that can easily be modified for long-term release profiles. Glycosaminoglycans (GAGs) have been known for their affinity for various cytokines and chemokines, including native RANTES, or CCL5. In this work, we investigated used of GAGs in generating a chemokine drug delivery device. Initial studies used surface plasmon resonance analysis to characterize and compare the affinities of different GAGs to 5P12-RANTES. These different GAGs were then incorporated into drug delivery polymeric hydrogels to engineer sustained release of the chemokines. In vitro release studies of 5P12-RANTES from the resulting polymers were performed, and we found that 5P12-RANTES release from these polymers can be controlled by the amount and type of GAG incorporated. Polymer disks containing GAGs with stronger affinity to 5P12-RANTES resulted in more sustained and longer term release than did polymer disks containing GAGs with weaker 5P12-RANTES affinity. Similar trends were observed by varying the amount of GAGs incorporated into the delivery system. 5P12-RANTES released from these polymers demonstrated good levels of CCR5 blocking, retaining activity even after 30 days of incubation.

Polymer Additives to Personal Protective Equipment can Inactivate Pathogens.

Face masks have been proven to be medicine's best public health tool for preventing transmission of airborne pathogens. However, in situations with continuous exposure, lower quality and "do-it-yourself" face masks cannot provide adequate protection against pathogens, especially when mishandled. In addition, the use of multiple face masks each day places a strain on personal protective equipment (PPE) supply and is not environmentally sustainable. Therefore, there is a significant clinical and commercial need for a reusable, pathogen-inactivating face mask. Herein, we propose adding quaternary poly(dimethylaminohexadecyl methacrylate), q(PDMAHDM), abbreviated to q(PDM), to existing fabric networks to generate "contact-killing" face masks-effectively turning cotton, polypropylene, and polyester into pathogen resistant materials. It was found that q(PDM)-integrated face masks were able to inactivate both Gram-positive and Gram-negative bacteria in liquid culture and aerosolized droplets. Furthermore, q(PDM) was electrospun into homogeneous polymer fibers, which makes the polymer practical for low-cost, scaled-up production.

Microparticle delivery of Interleukin-7 to boost T-cell proliferation and survival.

In HIV infections, homoeostasis of T cells is dysregulated such that there is a depletion of CD4(+) T cells and a progressive loss of naïve CD4(+) and CD8(+) T cells. Methodologies that can improve the function of some or all of these cells will likely enhance immune responsiveness in HIV infection. Interleukin-7 (IL-7) is a cytokine that has been shown to be critical in homeostatic expansion of naïve CD8(+) and CD4(+) cells in lymphopenic hosts, as well as regulating effector T cell to memory T-cell transition and memory T-cell homeostasis. In animal studies and clinical trials, repeated injections of IL-7 are used to boost both CD4(+) and CD8(+) cell counts. Daily injections, however, are painful, inconvenient, and provide a frequent route for pathogen entry. We developed a poly (D,L-lactide-co-glycolide; PLGA) microparticle controlled release system to administer IL-7 in which a single injection of microparticles can provide therapeutic delivery of IL-7. IL-7 encapsulated PLGA microparticles were first synthesized using a water/organic/water double emulsion method, release from the particles was then optimized using in vitro release studies and therapeutic effectiveness was finally studied in animal studies. These PLGA microparticles showed effective delivery of IL-7 for 1 week in vitro. These results were translated to in vivo delivery as well, which was followed for 9 days. Controlled release of IL-7 in mice demonstrated biological activity in both CD4(+) and CD8(+) T cells in mice, which was consistent with previously reported results using daily injections.

Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics.

While peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient to treat diseases that require sustained, local release of therapeutics. Cyclodextrin-based polymers (pCD) have been utilized as a platform to extend the local delivery of small-molecule hydrophobic drugs by leveraging hydrophobic-driven thermodynamic interactions between pCD and payload to extend its release, which has seen success both in vitro and in vivo. Herein, we proposed the novel synthesis of protein-polymer conjugates that are capped with a "high affinity" adamantane. Using bovine serum albumin as a model protein, and anti-interleukin 10 monoclonal antibodies as a functional example, we outline the synthesis of novel protein-polymer conjugates that, when coupled with cyclodextrin delivery platforms, can maintain a sustained release of up to 65 days without largely sacrificing protein structure/function which has significant clinical applications in local antibody-based treatments for immune diseases, cancers, and diabetes.

Grafting of short elastin-like peptides using an electric field.

Surface-grafted elastin has found a wide range of uses such as sensing, tissue engineering and capture/release applications because of its ability to undergo stimuli-responsive phase transition. While various methods exist to control surface grafting in general, it is still difficult to control orientation as attachment occurs. This study investigates using an electric field as a new approach to control the surface-grafting of short elastin-like polypeptide (ELP). Characterization of ELP grafting to gold via quartz crystal microbalance with dissipation, atomic force microscopy and temperature ramping experiments revealed that the charge/hydrophobicity of the peptides, rearrangement kinetics and an applied electric field impacted the grafted morphology of ELP. Specifically, an ELP with a negative charge on the opposite end of the surface-binding moiety assembled in a more upright orientation, and a sufficient electric field pushed the charge away from the surface compared to when the same peptide was assembled in no electric field. In addition, this study demonstrated that assembling charged ELP in an applied electric field impacts transition behavior. Overall, this study reveals new strategies for achieving desirable and predictable surface properties of surface-bound ELP.

PMMA Bone Cement Composite Functions as an Adjuvant Chemotherapeutic Platform for Localized and Multi-Window Release during Bone Reconstruction.

Primary bone tumor resections often result in critical size defects, which then necessitate challenging clinical management approaches to reconstruct. One such intervention is the Masquelet technique, in which poly(methyl methacrylate) (PMMA) bone cement is placed as a spacer temporarily while adjuvant chemotherapeutics are administered systemically. The spacer is later removed and replaced with bone autograft. Local recurrence remains an important and devastating problem, therefore, a system capable of locally delivering chemotherapeutics will present unique advantages. In this work, a refillable chemotherapeutic (doxorubicin, DOX) delivery platform comprised of PMMA bone cement and insoluble γ-cyclodextrin (γ-CD) polymeric microparticles is developed and explored towards application as a temporary adjuvant chemotherapeutic spacer. The system is characterized for porosity, mechanical strength, DOX filling and refilling capacity, elution kinetics, and cytotoxicity. Since residual chemotherapeutics can adversely impact bone healing, it is important that virtually all DOX be released from material. Composites containing 15 wt% γ-CD microparticles demonstrate 100% DOX release within 100 days, whereas only 6% DOX is liberated from PMMA with free DOX over same period. Refillable properties of PMMA composite system may find utility for customizing dosing regimens. Findings suggest that PMMA composites can have potential as chemotherapeutic delivery platforms to assist in bone reconstruction.

Injectable Extracellular Matrix Microparticles Promote Heart Regeneration in Mice with Post-ischemic Heart Injury.

Ischemic heart injury causes permanent cardiomyocyte loss and fibrosis impairing cardiac function. Tissue derived biomaterials have shown promise as an injectable treatment for the post-ischemic heart. Specifically, decellularized extracellular matrix (dECM) is a protein rich suspension that forms a therapeutic hydrogel once injected and improves the heart post-injury response in rodents and pig models. Current dECM-derived biomaterials are delivered to the heart as a liquid dECM hydrogel precursor or colloidal suspension, which gels over several minutes. To increase the functionality of the dECM therapy, an injectable solid dECM microparticle formulation derived from heart tissue to control sizing and extend stability in aqueous conditions is developed. When delivered into the infarcted mouse heart, these dECM microparticles protect cardiac function promote vessel density and reduce left ventricular remodeling by sustained delivery of biomolecules. Longer retention, higher stiffness, and slower protein release of dECM microparticles are noted compared to liquid dECM hydrogel precursor. In addition, the dECM microparticle can be developed as a platform for macromolecule delivery. Together, the results suggest that dECM microparticles can be developed as a modular therapy for heart injury.

Affinity-Based Polymers Provide Long-Term Immunotherapeutic Drug Delivery Across Particle Size Ranges Optimal for Macrophage Targeting.

Drug delivery to specific arms of the immune system can be technically challenging to provide prolonged drug release while limiting off-target toxicity given the limitations of current drug delivery systems. In this work, we test the design of a cyclodextrin (CD) polymer platform to extend immunomodulatory drug delivery via affinity interactions for sustained release at multiple size scales. The parameter space of synthesis variables influencing particle nucleation and growth (pre-incubation time and stirring speed) and post-synthesis grinding effects on resulting particle diameter were characterized. We demonstrate that polymerized CD forms exhibit size-independent release profiles of the small molecule drug lenalidomide (LND) and can provide improved drug delivery profiles versus macro-scale CD polymer disks in part due to increased loading efficiency. CD polymer microparticles and smaller, ground particles demonstrated no significant cytotoxicity as compared to the base CD monomer when co-incubated with fibroblasts. Uptake of ground CD particles was significantly higher following incubation with RAW 264.7 macrophages in culture over standard CD microparticles. Thus, the affinity/structure properties afforded by polymerized CD allow particle size to be modified to affect cellular uptake profiles independently of drug release rate for applications in cell-targeted drug delivery.

Recent Advances in the Evaluation of Antimicrobial Materials for Resolution of Orthopedic Implant-Associated Infections In Vivo.

While orthopedic implant-associated infections are rare, revision surgeries resulting from infections incur considerable healthcare costs and represent a substantial research area clinically, in academia, and in industry. In recent years, there have been numerous advances in the development of antimicrobial strategies for the prevention and treatment of orthopedic implant-associated infections which offer promise to improve the limitations of existing delivery systems through local and controlled release of antimicrobial agents. Prior to translation to in vivo orthopedic implant-associated infection models, the properties (e.g., degradation, antimicrobial activity, biocompatibility) of the antimicrobial materials can be evaluated in subcutaneous implant in vivo models. The antimicrobial materials are then incorporated into in vivo implant models to evaluate the efficacy of using the material to prevent or treat implant-associated infections. Recent technological advances such as 3D-printing, bacterial genomic sequencing, and real-time in vivo imaging of infection and inflammation have contributed to the development of preclinical implant-associated infection models that more effectively recapitulate the clinical presentation of infections and improve the evaluation of antimicrobial materials. This Review highlights the advantages and limitations of antimicrobial materials used in conjunction with orthopedic implants for the prevention and treatment of orthopedic implant-associated infections and discusses how these materials are evaluated in preclinical in vivo models. This analysis serves as a resource for biomaterial researchers in the selection of an appropriate orthopedic implant-associated infection preclinical model to evaluate novel antimicrobial materials.