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Post traumatic osteoarthritis (PTOA) is the result of a joint trauma or injury and accounts for 12.5% of all OA cases. Following joint trauma, inflammatory cytokines are produced and stimulate the secretion of catabolic enzymes that degrade articular cartilage. The degraded articular cartilage further stimulates catabolic enzyme and inflammatory cytokine expression. These lead to the development of the inflammatory cycle associated with PTOA. We hypothesized that inhibiting inflammation and treating the damaged cartilage may prevent the progression of PTOA and restore functionality to osteoarthritic cartilage using nanoparticle-peptide therapeutics.The first study developed polymeric core-shell nanoparticles composed of N-isopropyl acrylamide (NIPAm), N, N′-bis (acryloyl) cystamine (BAC), 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), and acrylic acid (AAc) (poly(NIPAm-co-AMPS-BAC-AAc)) by exploiting the thermoresponsive behavior of NIPAm. NIPAm has a lower critical solution temperature (LCST) of 32°C. Below the LCST, NIPAm is hydrophilic and causes the particle to swell, and above the LCST is hydrophobic and causes the particle to constrict. Poly(NIPAm-co-AMPS-BAC-AAc) shells were crosslinked around the hydrophobically stabilized non-crosslinked poly(NIPAm) (pNIPAm) cores above the LCST of NIPAm. Removal of the cores via diffusion resulted in thermoresponsive, degradable nanoparticles with low density, termed hollow, cores. The hollow nanoparticles (hNPs) encapsulated more of the anti-inflammatory MK2 inhibiting (MK2i) peptide than solid nanoparticles, and loaded roughly 2.5 times more MK2i below the LCST of NIPAm than above it. These hNPs loaded with MK2i inhibited IL-6 production in stimulated bovine chondrocytes in vitro. The hNPs were also retained within the joint space of rats for 7 days. These results show the ability of MK2i loaded hNPs to inhibit inflammation and show that the drug-loaded hNPS have potential as a therapeutic to treat PTOA.We also showed the ability of hNPs to be conjugated with the hyaluronic acid (HA) binding peptide GAHWQFNALTVRGSG (GAH). AAc served as the carboxylate anchor within the shell of the hNP and allowed for GAH conjugation. hNPs conjugated with roughly 19 GAH, termed 19 GAH-hNP, bound to HA in solution and resulted in a 94.0% increase in dynamic viscosity compared to the HA solution treated with unconjugated hNPs. Bovine cartilage explants were treated with trypsin to remove aggrecan and served as an ex vivo model for OA. The aggrecan-depleted (AD) explants treated with 0.10 mg of unconjugated hNPs had a muted effect on restoring compressive strength and suppression of CS release, likely due to reduced HA interactions. While the AD explants treated with 0.10 mg of 19 GAH-hNP restored the compressive strength to healthy levels 6 days after a single treatment and inhibited degradation of the ECM of cartilage. Based on these results, treatment with 19 GAH-hNP may be able to prevent the development of PTOA.Finally, the MK2i loaded hNP (hNP+MK2i) and hNPs were tested in a small animal in vivo study. Previous research developed a physiologically relevant non-invasive ACL rupture (NIACLR) model using a tibial compression to tear the ACL. We attempted to utilize this model to test the efficacy of our hNP+MK2i therapeutic to inhibit the progression of PTOA in vivo. However, only 9 of the 28 rats that underwent tibial compression resulted in a complete ACL tear, and we were not able to quantify the efficacy of our hNP+MK2i therapeutic.These data presented here suggests the use of nanoparticle-peptide therapeutics may be a translatable platform to inhibit the progression of PTOA.

Joint trauma results in the production of inflammatory cytokines that stimulate the secretion of catabolic enzymes, which degrade articular cartilage. Molecular fragments of the degraded articular cartilage further stimulate inflammatory cytokine production, with this process eventually resulting in post-traumatic osteoarthritis (PTOA). The loss of matrix component aggrecan occurs early in the progression of PTOA and results in the loss of compressive stiffness in articular cartilage. Aggrecan is highly sulfated, associates with hyaluronic acid (HA), and supports the compressive stiffness in cartilage. Presented here, we conjugated the HA-binding peptide GAHWQFNALTVRGSG (GAH) to anionic nanoparticles (hNPs). Nanoparticles conjugated with roughly 19 GAH peptides, termed 19 GAH-hNP, bound to HA in solution and increased the dynamic viscosity by 94.1% compared to an HA solution treated with unconjugated hNPs. Moreover, treating aggrecan-depleted (AD) cartilage explants with 0.10 mg of 19 GAH-hNP restored the cartilage compressive stiffness to healthy levels six days after a single nanoparticle treatment. Treatment of AD cartilage with 0.10 mg of 19 GAH-hNP inhibited the degradation of articular cartilage. Treated AD cartilage had 409% more collagen type II and 598% more GAG content than untreated-AD explants. The 19 GAH-hNP therapeutic slowed ECM degradation in AD cartilage explants, restored the compressive stiffness of damaged cartilage, and showed promise as a localized treatment for PTOA.

Inflammation following joint trauma contributes to cartilage degradation and progression of post traumatic osteoarthritis (PTOA). Therefore, drug delivery vehicles that deliver effective anti-inflammatory treatments have the potential to prevent PTOA. We have developed solid and hollow, thermoresponsive nanoparticles for the controlled release of our anti-inflammatory MK2-inhibiting (MK2i) peptide for intra-articular injection to halt inflammation that contributes to the advancement of PTOA. This system exploits the thermosensitive characteristic of N-isopropyl acrylamide (NIPAm) to transition phases when passing through its lower critical solution temperature (LCST). The nanoparticles (NPs) swell below the LCST and constrict above it. Non-crosslinked poly(NIPAm) (pNIPAm), held above its LCST, formed hydrophobic cores around which shells composed of NIPAm, degradable crosslinker N, N′-bis (acryloyl) cystamine (BAC), sulfated 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), and acrylic acid (AAc) were polymerized. Removal of the non-crosslinked pNIPAm cores via diffusion produced thermosensitive, degradable nanoparticles with low density, or hollow, cores. The data presented here revealed low-density, termed hollow, nanoparticles (hNPs) load and release significantly more MK2i than solid nanoparticles (sNPs). Furthermore, drug loading below the LCST of NIPAm results in roughly 2.5 times more therapeutic encapsulation compared to loading particles in their constricted state. Hollow nanoparticles increase drug loading compared to solid nanoparticles, are taken up into chondrocytes within 24 h, cleared from the cells within 6 days, significantly decrease the secretion of the proinflammatory cytokine IL-6, and, via intra-articular injection, are successfully delivered into the joint space of rats. The peptide loaded nanoparticles provide a reproducible platform for intra-articular delivery of therapeutics.

Background:Ventriculoperitoneal shunts (VPSs) have been the mainstay of treating hydrocephalus since the 1950s. However, shunts have a reported complication rate reaching nearly 50%. Devices have been developed that utilize noninvasive thermal transcutaneous diffusion technology. These shunt evaluation devices measure temperature gradients to detect shunt cerebrospinal fluid flow. We assessed the utility using a thermal diffusion technique to work up shunt failure in the emergency room (ER).Methods:This was a retrospective case series at a single medical center ER. We included consecutive patients with possible VPS malfunction who were evaluated with a thermal sensor. The time period of data collection included September 2015–April 2018.Results:Eight patients were reviewed, including four males and four females. The average age of reviewed patients was 35.1 (+/− ; 16.5). In our case series, three patients had adequate shunt flow as assessed by the shunt evaluation device, and the decision was made to discharge the patient and follow-up in clinic. In two patients, the flow was diminished, but due to other reassuring signs, the patients were still discharged with follow-up. Two patients were noted to have poor flow and were admitted for shunt revision.Conclusion:It is important to determine whether a malfunction is present and whether an intervention is necessary for patients who present to the emergency department with possible symptoms of shunt failure. A thermal sensor is a fast and noninvasive tool in the evaluation of shunt flow and helps determine whether it is safe to send a patient home or intervene appropriately.