Oxidatively degradable poly(thioketal urethane)/ceramic composite bone cements with bone-like strength

Abstract

Synthetic bone cements are commonly used in orthopaedic procedures to aid in bone regeneration following trauma or disease. Polymeric cements like PMMA provide the mechanical strength necessary for orthopaedic applications, but they are not resorbable and do not integrate with host bone. Ceramic cements have a chemical composition similar to that of bone, but their brittle mechanical properties limit their use in weight-bearing applications. In this study, we designed oxidatively degradable, polymeric bone cements with mechanical properties suitable for bone tissue engineering applications. We synthesized a novel thioketal (TK) diol, which was crosslinked with a lysine triisocyanate (LTI) prepolymer to create hydrolytically stable poly(thioketal urethane)s (PTKUR) that degrade in the oxidative environment associated with bone defects. PTKUR films were hydrolytically stable for up to 6 months, but degraded rapidly (<1 week) under simulated oxidative conditions in vitro. When combined with ceramic micro- or nanoparticles, PTKUR cements exhibited working times comparable to calcium phosphate cements and strengths exceeding those of trabecular bone. PTKUR/ceramic composite cements supported appositional bone growth and integrated with host bone near the bone-cement interface at 6 and 12 weeks post-implantation in rabbit femoral condyle plug defects. Histological evidence of osteoclast-mediated resorption of the cements was observed at 6 and 12 weeks. These findings demonstrate that a PTKUR bone cement with bone-like strength can be selectively resorbed by cells involved in bone remodeling, and thus represent an important initial step toward the development of resorbable bone cements for weight-bearing applications.

Resorbable nanocomposites with bone-like strength and enhanced cellular activity

“…In oxidative medium, the nHA-LTI nanocomposite degraded faster than the LTI-PEUR polymer, which degraded <10% after 21 days. 59,60 The faster rate of degradation in oxidative compared to hydrolytic medium is consistent with the observed resorption of nHA-LTI by osteoclasts, which secrete reactive oxygen species (ROS) during bone remodeling. 61–64 The combination of enhanced mineralization by osteoblasts and osteoclast-mediated resorption is anticipated to minimize resorption and fibrous scar formation in vivo by aligning the rates of new bone formation and graft resorption.…”

“…67–69 While the biocompatibility of injectable nHA-PEUR nanocomposites was not directly assessed in this study, previous work from our group and others’ has reported that reactive lysine-derived polyurethanes do not release cytotoxic components or large amounts of heat that damage cells and host tissue. 48,60,70–74 …”

Layer‐by‐Layer Cerium Oxide Nanoparticle Coating for Antioxidant Protection of Encapsulated Beta Cells

“…. For cellular encapsulation, groups have also screened materials that contain inherent antioxidant properties or have been modified to scavenge ROS, e.g., poly(propylene sulfate), poly(thioketal urethane), and CONP encapsulated in alginate. [9b]…”

Oxidation‐Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues

“…Their oxidative response (right) is mechanistically not well characterized, but is generally assumed to generate hemithioketal intermediates through the attack of, for example, OH radicals, eventually leading to double chain scission and production of acetone and thiols; it is, however, likely that also peroxide derivatives of acetone and oxidized thiols are produced, the latter possibly in the form of (mixed) disulfides. B) Double OH‐terminated thioketals can be produced to yield monomers or macromonomers to yield polyurethanes after reactions with di‐ or triisocyanates; also heterofunctional thioketals can also be prepared, for example, containing a carboxylic acid and a protected amine, although through the process is more cumbersome and has low yields (always ≪50%) …”

“…Last, it is worth mentioning the work of Duvall's group, which employed poly(thioketal urethane)s obtained from the reaction of thioketal macrodiols with isocyanates (Figure B); by varying the structure of the macrodiol, cross‐linked polymers can be produced of variable hydrophilicity and processed in the form of sponges. These materials showed gradual cellular infiltration and ROS‐ (and therefore cell‐mediated), but not unspecific, hydrolytic degradation in rat wound models and bone defects; the possibility of hydrolytic degradation can be introduced by the appropriate choice of a degradable isocyanate (lysine triisocyanate) …”