In vivo biodistribution and clearance of peptide amphiphile micelles.

Peptide amphiphiles (PAs) are promising biomaterials for medical applications. To translate the use of PAs successfully from laboratories to clinics, in vivo studies regarding the safety of these nanomaterials are required. To examine the toxicity and clearance of PA biomaterials, we intravenously administered cy7-labeled, spherical PA micelles, control micelles without a peptide sequence, or PBS in a murine model and investigated biocompatibility, biodistribution, and clearance. Both peptide and non-peptide labeled micelles were approximately 8 nm in diameter, but of opposite surface charge. Neither micelle type caused aggregation or hemolysis of red blood cells. All micelles primarily accumulated in the bladder and were present in urine samples confirming elimination through renal clearance. Ex vivo imaging showed that micelles were also found in the liver suggesting some involvement of the reticuloendothelial system. However, no evidence of toxicity was found within the liver, spleen, kidney, bladder, intestines, lung, and heart. FROM THE CLINICAL EDITOR: Safety studies related to peptide amphiphile biomaterials are discussed in this paper, demonstrating that organotoxicity is unlikely with these materials, however, RES activation in the liver may be of consideration in further studies and needed for potential applications.

A biodegradable tri-component graft for anterior cruciate ligament reconstruction.

Bone-patellar tendon-bone (BPTB) autografts are the gold standard for anterior cruciate ligament (ACL) reconstruction because the bony ends allow for superior healing and anchoring through bone-to-bone regeneration. However, the disadvantages of BPTB grafts include donor site morbidity and patellar rupture. In order to incorporate bone-to-bone healing without the risks associated with harvesting autogenous tissue, a biodegradable and synthetic tri-component graft was fabricated, consisting of porous poly(1,8-octanediol-co-citric acid)-hydroxyapatite nanocomposites (POC-HA) and poly(l-lactide) (PLL) braids. All regions of the tri-component graft were porous and the tensile properties were in the range of the native ACL. When these novel grafts were used to reconstruct the ACL of rabbits, all animals after 6 weeks were weight-bearing and showed good functionality. Histological assessment confirmed tissue infiltration throughout the entire scaffold and tissue ingrowth and interlocking within the bone tunnels, which is favourable for graft fixation. In conclusion, this pilot study suggests that a tri-component, biodegradable graft is a promising strategy to regenerate tissue types necessary for ACL tissue engineering, and provides a basis for developing an off-the-shelf graft for ACL repair. Copyright © 2014 John Wiley & Sons, Ltd.

Monocyte-targeting supramolecular micellar assemblies: a molecular diagnostic tool for atherosclerosis.

Atherosclerosis is a multifactorial inflammatory disease that can progress silently for decades and result in myocardial infarction, stroke, and death. Diagnostic imaging technologies have made great strides to define the degree of atherosclerotic plaque burden through the severity of arterial stenosis. However, current technologies cannot differentiate more lethal "vulnerable plaques," and are not sensitive enough for preventive medicine. Imaging early molecular markers and quantifying the extent of disease progression continues to be a major challenge in the field. To this end, monocyte-targeting, peptide amphiphile micelles (PAMs) are engineered through the incorporation of the chemokine receptor CCR2-binding motif of monocyte chemoattractant protein-1 (MCP-1) and MCP-1 PAMs are evaluated preclinically as diagnostic tools for atherosclerosis. Monocyte-targeting is desirable as the influx of monocytes is a marker of early lesions, accumulation of monocytes is linked to atherosclerosis progression, and rupture-prone plaques have higher numbers of monocytes. MCP-1 PAMs bind to monocytes in vitro, and MCP-1 PAMs detect and discriminate between early- and late-stage atherosclerotic aortas. Moreover, MCP-1 PAMs are found to be eliminated via renal clearance and the mononuclear phagocyte system (MPS) without adverse side effects. Thus, MCP-1 PAMs are a promising new class of diagnostic agents capable of monitoring the progression of atherosclerosis.

The role of hydroxyapatite in citric acid-based nanocomposites: surface characteristics, degradation, and osteogenicity in vitro.

The incorporation of nanoscale hydroxyapatite (HA) into biodegradable polymers can potentially mimic the native structure of bone and influence the mechanical properties and the extent of bioactivity. In this study nanocomposites of poly(1,8-octanediol-co-citrate) (POC) containing 40, 50, and 60 wt.% HA (POC-HA) were fabricated and characterized. Nanocomposite hydrophilicity and the degradation properties in vitro were evaluated via contact angle measurements, scanning electron microscopy (SEM), and mass loss measurements. Human mesenchymal stem cells (hMSC) were cultured on POC-HA nanocomposites in both growth and osteogenic media. Cell proliferation, alkaline phosphatase activity, and osteocalcin were measured. The equilibrium water in air contact angles confirmed all of the nanocomposites to be hydrophilic (23.4 ± 8.1°, 27 ± 9.1°, and 27.7 ± 3.5° for 40, 50, and 60 wt.% HA, respectively). Over a period of 26 weeks the degradation rate increased with decreasing HA content and pore formation was evident for POC-HA containing 40 wt.% HA, whereas POC with 50 and 60 wt.% HA lacked pores (mass loss at 26 weeks for 40, 50, and 60 wt.% HA, 27.4 ± 1.6%, 17.7 ± 1.6%, and 6.3 ± 2.6%, respectively). hMSC adhered and proliferated well on all composites, confirming biocompatibility for at least 21 days. An increase in adhesion and proliferation was found with increasing HA nanoparticle content (ng DNA at day 21 for 40, 50, and 60 wt.% HA, 130.4 ± 49.4, 184.4 ± 86.4, 314.1 ± 92.3). Alkaline phosphatase activity and osteocalcin concentration correlated with HA content (alkaline phosphate activity in expansion medium and osteogenic medium for 40, 50, and 60 wt.% HA, 256.1 ± 71.8%, 304.0 ± 128.7%, and 500.2 ± 89.9%, and 358.4 ± 124.1%, 653.7 ± 216.5%, and 814.4 ± 68.8%, respectively; osteocalcin concentration in expansion medium and osteogenic medium for 40, 50, and 60 wt.% HA, 236.9 ± 7.8%, 253.0 ± 7.5%, and 285.2 ± 11.4%, and 265.8 ± 15.0%, 288.3 ± 17.9%, and 717.3 ± 38.7%, respectively). This study provides insight into how the HA nanoparticle content can modulate the cell compatibility and physical properties of POC-HA nanocomposites.