Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct advantages over traditional antibiotics. Antimicrobial peptides are found in all forms of life and demonstrate a pivotal role in the innate immune system. Many antimicrobial peptides are evolutionarily conserved, with limited propensity for resistance. Additionally, chemical modifications to the peptide backbone can be used to improve biological activity and stability and reduce toxicity. This review details the therapeutic potential of peptide-based antimicrobials, as well as the challenges needed to overcome in order for clinical translation. We explore the proposed mechanisms of activity, design of synthetic biomimics, and how this novel class of antimicrobial compound may address the need for effective antibiotics. Finally, we discuss commercially available peptide-based antimicrobials and antimicrobial peptides in clinical trials.

Numerous procedures have been described for the operative management of acromioclavicular joint injuries, but surprisingly little information is available on the ultimate mechanical behavior of the native coracoclavicular ligament complex or on the various methods of reconstruction. We tested 19 fresh-frozen cadaveric bone-ligament-bone preparations of the coracoclavicular ligament in uniaxial tension at 25 mm/min until failure. Seven specimens were left intact, six had the trapezoid ligament sectioned, and six had the conoid ligament sectioned. Reconstruction of the coracoclavicular ligament was achieved using coracoacromial ligament transfers, woven polyester slings, suture anchors, and Bosworth screws; all reconstructions were also tested to failure. The intact coracoclavicular ligament failed by avulsion or midsubstance tear at 500 (+/-134) N, with a stiffness of 103 (+/-30) N/mm and elongation to failure of 7.7 (+/-1.9) mm. There was no significant difference between the contributions of the conoid or trapezoid ligaments in this loading configuration. Coracoclavicular slings and suture anchors provided strength similar to that of the coracoclavicular ligament, but with significantly greater deformations (14 to 26 mm). Screw fixation resulted in comparable stiffness and superior strength to the coracoclavicular ligament, but only if bicortical purchase was obtained. Coracoacromial ligament transfers were the weakest and least stiff, and augmentation with another form of coracoclavicular fixation is recommended. These results provide a useful baseline for comparison of the initial performance of reconstructive techniques with the performance of the native coracoclavicular ligament.

The clinical outcome of lumbar spinal fusion is correlated with achievement of bony fusion. Improving interbody implant bone on-growth and in-growth may enhance fusion, limiting pseudoarthrosis, stress shielding, subsidence and implant failure. Polyetheretherketone (PEEK) and titanium (Ti) are commonly selected for interbody spacer construction. Although these materials have desirable biocompatibility and mechanical properties, they require further modification to support osseointegration. Reports of extensive research on this topic are available in biomaterial-centric published reports; however, there are few clinical studies concerning surface modification of interbody spinal implants. The current article focuses on surface modifications aimed at fostering osseointegration from a clinician's point of view. Surface modification of Ti by creating rougher surfaces, modifying its surface topography (macro and nano), physical and chemical treatment and creating a porous material with high interconnectivity can improve its osseointegrative potential and bioactivity. Coating the surface with osteoconductive materials like hydroxyapatite (HA) can improve osseointegration. Because PEEK spacers are relatively inert, creating a composite by adding Ti or osteoconductive materials like HA can improve osseointegration. In addition, PEEK may be coated with Ti, effectively bio-activating the coating.

Achieving a stable bone-implant interface is an important factor in the long-term outcome of joint arthroplasty. In this study, we employed an ovine bicortical model to compare the bone-healing response to five different surfaces on titanium alloy implants: grit blasted (GB), grit blasted plus hydroxyapatite (50 microm thick) coating (GBHA), Porocoat(R) (PC), Porocoat(R) with HA (PCHA) and smooth (S). Push-out testing, histology, and backscatter scanning electron microscope (SEM) imaging were employed to assess the healing response at 4, 8, and 12 weeks. Push-out testing revealed PC and PCHA surfaces resulted in significantly greater mechanical fixation over all other implant types at all time points (p <.05). HA coating on the grit-blasted surface significantly improved fixation at 8 and 12 weeks (p <.05). The addition of HA onto the porous coating did not significantly improve fixation in this model. Quantification of ingrowth/ongrowth from SEM images revealed that HA coating of the grit-blasted surfaces resulted in significantly more ongrowth at 4 weeks (p <.05).

The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.

Lung function, acute pulmonary exacerbations (APE), and weight are the best clinical predictors of survival in cystic fibrosis (CF); however, underlying mechanisms are incompletely understood. Biomarkers of current disease state predictive of future outcomes might identify mechanisms and provide treatment targets, trial endpoints and objective clinical monitoring tools. Such CF-specific biomarkers have previously been elusive. Using observational and validation cohorts comprising 97 non-transplanted consecutively-recruited adult CF patients at the Intermountain Adult CF Center, University of Utah, we identified biomarkers informative of current disease and predictive of future clinical outcomes. Patients represented the majority of sputum producers. They were recruited March 2004-April 2007 and followed through May 2011. Sputum biomarker concentrations were measured and clinical outcomes meticulously recorded for a median 5.9 (interquartile range 5.0 to 6.6) years to study associations between biomarkers and future APE and time-to-lung transplantation or death. After multivariate modeling, only high mobility group box-1 protein (HMGB-1, mean = 5.84 [log ng/ml], standard deviation [SD] = 1.75) predicted time-to-first APE (hazard ratio [HR] per log-unit HMGB-1 = 1.56, p-value = 0.005), number of future APE within 5 years (0.338 APE per log-unit HMGB-1, p<0.001 by quasi-Poisson regression) and time-to-lung transplantation or death (HR = 1.59, p = 0.02). At APE onset, sputum granulocyte macrophage colony stimulating factor (GM-CSF, mean 4.8 [log pg/ml], SD = 1.26) was significantly associated with APE-associated declines in lung function (−10.8 FEV1% points per log-unit GM-CSF, p<0.001 by linear regression). Evaluation of validation cohorts produced similar results that passed tests of mutual consistency. In CF sputum, high HMGB-1 predicts incidence and recurrence of APE and survival, plausibly because it mediates long-term airway inflammation. High APE-associated GM-CSF identifies patients with large acute declines in FEV1%, possibly providing a laboratory-based objective decision-support tool for determination of an APE diagnosis. These biomarkers are potential CF reporting tools and treatment targets for slowing long-term progression and reducing short-term severity.

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