Effect of Lubricin Mimetics on the Inhibition of Osteoarthritis in a Rat Anterior Cruciate Ligament Transection Model.

BACKGROUND: Lubricin, a mucinous glycoprotein, plays a chondroprotective role as a constituent of synovial fluid. Structural analogs have been synthesized to mimic the structure and function of native lubricin in an effort to recapitulate this effect with the goal of delaying progression of osteoarthritis (OA). PURPOSE: To investigate the efficacy of intra-articular injections of lubricin mimetics in slowing or preventing the progression of posttraumatic OA by using a rat anterior cruciate ligament transection model. STUDY DESIGN: Controlled laboratory design. METHODS: Four lubricin mimetics were investigated, differing from one another in their binding orientations and steric interactions. Eighty skeletally mature Sprague-Dawley rats underwent bilateral anterior cruciate ligament transections and were randomly allocated to receive intra-articular injections (50 µL/injection) of 1 of the 4 mimetics in the right knee and equal volumes of saline injection in the contralateral knee (control). All rats were euthanized 8 weeks postoperatively and assessed via biomechanical analysis, which evaluated comparative friction coefficients across the 4 groups, and histological evaluation of articular cartilage, osteophytes, and synovitis. The Osteoarthritis Research Society International (OARSI) histopathological assessment system was used to evaluate the degree of articular cartilage degeneration and osteophytes, while synovitis was assessed through a semiquantitative scoring system. Binding efficacy of the 4 mimetics was assessed in vitro and in vivo through the immunohistochemical localization of polyethylene glycol. Articular cartilage degeneration and synovitis scoring data analyses were performed with generalized estimating equation modeling. RESULTS: Injection of the group 3 mimetic (random 24 + 400 + 30) directly correlated with improved OARSI scores for femoral articular cartilage degeneration when compared with saline-injected contralateral control knees (P = .0410). No lubricin mimetic group demonstrated statistically significant differences in OARSI scores for tibial articular cartilage degeneration. Injection of the group 4 mimetic (AB 24 + 400 + 30) led to a statistically significant difference in osteophyte OARSI score (P = .0019). None of the 4 lubricin mimetics injections incited an additive synovial inflammatory response. Immunohistochemical staining substantiated the binding capacity of all 4 mimetics, while in vivo experimentation revealed that the group 1 and 3 mimetics were still retained within the joint 4 weeks after injection. There were no differences in friction coefficients between any pair of groups and no significant trends based on lubricin mimetic structure. CONCLUSION: We demonstrated that the tribosupplementation of a traumatically injured knee with a specific lubricin structural analog may attenuate the natural progression of OA. CLINICAL RELEVANCE: The current lack of efficacious clinical options to counter the onset and subsequent development of OA suggests that further investigation into the synthesis and behavior of lubricin analogs could yield novel translational applications.

Influence of Block Length on Articular Cartilage Lubrication with a Diblock Bottle-Brush Copolymer.

We report how the tribological properties of a class of diblock copolymers with architecture and function inspired by the lubricating glycoprotein lubricin correlate to chemical composition. This class of diblock copolymers, consisting of a cationic cartilage-binding block and a brush-lubricating block, demonstrates that boundary lubrication of articular cartilage more strongly depends on the cartilage-binding block than the lubrication block. Specifically, the cartilage-binding functional groups (tertiary or quaternary amines) and cartilage-binding block length significantly influence the degree of lubrication under boundary mode experimental conditions. An optimal number (∼24 in this case) of cartilage-binding groups led to the lowest coefficient of friction, and an increase or decrease in the number of cations in the binding block led to partial (>24, and between 12 and 24) or complete (=12) loss of lubricating ability. The length of the lubricating block (DP = 200 or 400) chosen in this study had no effect on the degree of lubrication. These results are put into context in terms of binding affinity to the cartilage and the spatial packing density of the polymer on the cartilage surface and can serve as a useful guide for future designs of synthetic lubricants that rival the efficacy of natural lubricants.

Boundary mode lubrication of articular cartilage with a biomimetic diblock copolymer.

We report the design of a diblock copolymer with architecture and function inspired by the lubricating glycoprotein lubricin. This diblock copolymer, synthesized by sequential reversible addition-fragmentation chain-transfer polymerization, consists of a cationic cartilage-binding domain and a brush-lubricating domain. It reduces the coefficient of friction of articular cartilage under boundary mode conditions (0.088 ± 0.039) to a level equivalent to that provided by lubricin (0.093 ± 0.011). Additionally, both the EC50 (0.404 mg/mL) and cartilage-binding time constant (7.19 min) of the polymer are comparable to purified human and recombinant lubricin. Like lubricin, the tribological properties of this polymer are dependent on molecular architecture. When the same monomer composition was evaluated either as an AB diblock copolymer or as a random copolymer, the diblock effectively lubricated cartilage under boundary mode conditions whereas the random copolymer did not. Additionally, the individual polymer blocks did not lubricate independently, and lubrication could be competitively inhibited with an excess of binding domain. This diblock copolymer is an example of a synthetic polymer with lubrication properties equal to lubricin under boundary mode conditions, suggesting its potential utility as a therapy for joint pathologies like osteoarthritis.

Transient phase behavior of an elastomeric biomaterial applied to abdominal laparotomy closure.

Secure closure of the fascial layers after entry into the peritoneal cavity is crucial to prevent incisional hernia, yet appropriate purchase of the tissue can be challenging due to the proximity of the underlying protuberant bowel which may become punctured by the surgical needle or strangulated by the suture itself. Devices currently employed to provide visceral protection during abdominal closure, such as the metal malleable retractor and Glassman Visceral Retainer, are unable to provide complete protection as they must be removed prior to complete closure. A puncture resistant, biocompatible, and degradable matrix that can be left in place without need for removal would facilitate rapid and safe abdominal closure. We describe a novel elastomer (CC-DHA) that undergoes a rapid but controlled solid-to-liquid phase transition through the application of a destabilized carbonate cross-linked network. The elastomer is comprised of a polycarbonate cross-linked network of dihydroxyacetone, glycerol ethoxylate, and tri(ethylene glycol). The ketone functionality of the dihydroxyacetone facilitates hydrolytic cleavage of the carbonate linkages resulting in a rapidly degrading barrier that can be left in situ to facilitate abdominal fascial closure. Using a murine laparotomy model we demonstrated rapid dissolution and metabolism of the elastomer without evidence of toxicity or intraabdominal scarring. Furthermore, needle puncture and mechanical properties demonstrated the material to be both compliant and sufficiently puncture resistant. These unique characteristics make the biomaterial extraordinarily useful as a physical barrier to prevent inadvertent bowel injury during fascial closure, with the potential for wider application across a variety of medical and surgical applications. STATEMENT OF SIGNIFICANCE: Fascial closure after abdominal surgery requires delicate maneuvers to prevent incisional hernia while minimizing risk for inadvertent bowel injury. We describe a novel biocompatible and biodegradable polycarbonate elastomer (CC-DHA) comprised of dihydroxyacetone, glycerol ethoxylate, and tri(ethylene glycol), for use as a rapidly degrading protective visceral barrier to aid in abdominal closure. Rapid polymer dissolution and metabolism was demonstrated using a murine laparotomy model without evidence of toxicity or intraabdominal scarring. Furthermore, mechanical studies showed the material to be sufficiently puncture resistant and compliant. Overall, this new biomaterial is extraordinary useful as a physical barrier to prevent inadvertent bowel injury during fascial closure, with the potential for wider application across a variety of medical and surgical applications.

Biohybrid -Se-S- coupling reactions of an amino acid derived seleninate.

We describe the synthesis of the N-(2-seleninatoethyl) amide of N-Boc-phenylalanine, serving here as a peptide model, and its reductive coupling reactions under mild conditions with unprotected thiouridine and glutathione. Selenosulfide products such as these comprise reversibly conjugated bio-components, and can potentially find uses as probes of biological function, such as enzyme inhibitors, delivery systems, or structural mimics.

Novel α-arylnitriles synthesis via Ni-catalyzed cross-coupling of α-bromonitriles with arylboronic acids under mild conditions.

An applicable and easy-handling Ni-catalyst can be used to promote direct arylation of α-bromonitriles with various arylboronic acids to construct α-arylnitriles under mild conditions. The methodology tolerates ß-hydrogens and functional groups in the substrates.