Minimally invasive injectable lumbar interbody fusion with mineralized collagen-modified PMMA bone cement: A new animal model.

This study was to develop a feasible and safe animal model for minimally invasive injectable lumbar interbody fusion using a novel biomaterial, mineralized collagen-polymethylmethacrylate bone cement (MC-PMMA), with unilateral pedicle screw fixation in an in vivo goat model. Eight goats (Capra aegagrus hircus) were divided into three groups: MC-PMMA, unmodified commercial-polymethylmethacrylate bone cement (UC-PMMA), and a control group (titanium cage filled with autogenous bone, TC-AB). Each group of goats was treated with minimally invasive lumbar interbody fusion at the L3/L4 and L5/L6 disc spaces (injected for MC-PMMA and UC-PMMA, implanted for TC-AB). The pedicle screws were inserted at the L3, L4, L5, and L6 vertebrae, respectively, and fixed on the left side. The characteristics of osteogenesis and bone growth were assessed at the third and the sixth month, respectively. The methods of evaluation included the survival of each animal, X-ray imaging, and 256-layer spiral computed tomography (256-CT) scanning, imaged with three-dimensional microfocus computed tomography (micro-CT), and histological analysis. The results showed that PMMA bone cement can be extruded smoothly after doping MC, the MC-PMMA integrates better with bone than the UC-PMMA, and all goats recovered after surgery without nerve damage. After 3 and 6 months, the implants were stable. New trabecular bone was observed in the TC-AB group. In the UC-PMMA group a thick fibrous capsule had formed around the implants. The MC-PMMA was observed to have perfect osteogenesis and bone ingrowth to adjacent bone surface. Minimally invasive injectable lumbar interbody fusion using MC-PMMA bone cement was shown to have profound clinical value, and the MC-PMMA showed potential application prospects.

Improved tumor tissue penetration and tumor cell uptake achieved by delayed charge reversal nanoparticles.

The high affinity of positively charged nanoparticles to biological interfaces makes them easily taken up by tumor cells but limits their tumor permeation due to non-specific electrostatic interactions. In this study, polyion complex coated nanoparticles with different charge reversal profiles were developed to study the influence of charge reversal profile on tumor penetration. The system was constructed by polyion complex coating using micelles composed of poly (lysine)-b-polycaprolactone (PLys-b-PCL) as the cationic core and poly (glutamic acid)-g- methoxyl poly (ethylene glycol) (PGlu-g-mPEG) as the anionic coating material. Manipulation of charge reversal profile was achieved by controlling the polymer chain entanglement and electrostatic interaction in the polyion complex layer through glutaraldehyde-induced shell-crosslinking. The delayed charge reversal nanoparticles (CTCL30) could maintain negatively charged in pH 6.5 PBS for at least 2h and exhibit pH-responsive cytotoxicity and cellular uptake in an extended time scale. Compared with a faster charge reversal counterpart (CTCL70) with similar pharmacokinetic profile, CTCL30 showed deeper penetration, higher in vivo tumor cell uptake and stronger antitumor activity in vivo (tumor inhibition rate: 72.3% vs 60.2%, compared with CTCL70). These results indicate that the delayed charge reversal strategy could improve therapeutic effect via facilitating tumor penetration. STATEMENT OF SIGNIFICANCE: Here, the high tumor penetration capability of PEG-coated nanoparticles and the high cellular uptake of cationic nanoparticles were combined by a delayed charge reversal drug delivery system. This drug delivery system was composed of a drug-loading cationic inner core and a polyion complex coating. Manipulation of charge reversal profile was realized by varying the crosslinking degree of the shell of the cationic inner core, through which changed the strength of the polyion complex layer. Nanoparticles with delayed charge reversal profile exhibited improved tumor penetration, in vivo tumor cell uptake and in vivo tumor growth inhibition effect although they have similar pharmacokinetic and biodistribution behaviors with their instant charge reversal counterpart.