The reinforces possibility satisfactory therapy await discovery fundamental proximal pathogenesis effects of LOX on other cells may need to be elucidated prior to conducting animal studies with this enzyme. A similar process would allow the identification of an optimal LOX concentration for maximizing the native-to-native integration strength; this will be immensely useful from a 
clinical perspective, once the safety and efficacy of exogenous LOX has been shown. While other cross-linkers such as ribose, glutaraldehyde, genipin, and methylglyoxal have all been investigated in conjunction with engineered articular cartilage, these agents have all been shown to alter cellular activity. Some of these agents are even cytotoxic and thus preclude their use with live cells in influencing integration. Furthermore, unnatural cross-linkers such as glutaraldehyde have been shown to elicit a foreign body giant cell reaction, in contrast to LOX, which is found naturally in multiple musculoskeletal tissues. This study demonstrates that LOX is a potent agent for enhancing integration between native and tissue engineered cartilage. It also paves the way for the use of LOX in improving native cartilage integration. These results could potentially be used to solve the problem of large cartilage defects by allowing tissue engineered cartilage implants to be integrated into the surrounding tissue. The multifunctional mannose 6 phosphate/insulin-like growth factor 2 receptor, hereafter referred to as IGF2R, mediates endocytosis and subsequent clearance or activation of a variety of ligands involved in the regulation of cell growth and motility, including insulin-like growth factor 2 and transforming growth factor b. The IGF2R gene shows developmental stage specific expression levels which are highest in the fetus and decline rapidly after birth. Murine Igf2r is imprinted and switches from biallelic to maternal expression during implantation. By the fetal stage, expression from the maternal allele is established in all tissues of the conceptus with the exception of brain, which escapes imprinting. In contrast, imprinting of IGF2R in human remains controversial, with exclusive biallelic expression, maternal or biallelic expression and partial imprinting reported for fetal and/or placental samples. The fundamental role of Igf2r in prenatal growth regulation suggests that quantitative variation in imprinting could affect phenotype via gene dosage effects. Indirect evidence for such an effect was obtained in the sheep model where fetal overgrowth induced by embryo culture was associated with hypomethylation at a CpG site in an intronic sequence element implicated in IGF2R imprinting and down regulated IGF2R expression. However, the imprinting status of IGF2R was not determined in this study. Species differences in imprinting, in particular in the placenta, appear to be linked to differences in reproductive strategies, e.g. litter size, gestational length, maturity of newborns and lifetime reproductive capability. The inconsistent data on IGF2R imprinting in human have been interpreted as evidence for a polymorphic trait, where the observed minority of imprinted or partially imprinted specimens could signal an evolutionary transition to biallelic expression in the population. It was further hypothesized that differences in imprinting of Igf2r/IGF2R between mouse and human could be a consequence of different reproductive strategies, including competition between multiple fetuses and the shorter gestation period requiring a more efficient placenta in mouse. However, comparative data from other species suitable for testing this hypothesis are lacking. The domestic cow has a similar gestation length as human, carries a single conceptus with comparable maturity at birth, has a similar lifetime reproductive capability, and shows a conserved IGF2R gene structure with high sequence homology to human.