Congenital pseudarthrosis of the tibia: what can we learn from computational models?

<p><strong>Introduction</strong></p> <p>Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself after birth by anterolateral bowing of the tibia and spontaneous tibial fractures [1]. Failure to maintain a bony union is however frequent, resulting in multiple revision surgeries and occasionally amputation. The exact etiology of CPT is still highly debated. However, 40-80% of the CPT-patients are carriers of a mutation in the Neurofibromatosis type 1 (NF1) gene potentially resulting in an altered phenotype of the skeletal cells and impaired bone healing. This study will use a multiscale computational model of bone regeneration to investigate the impaired healing in NF1 patients.</p> <p><strong>Experimental methods</strong></p> <p>In order to examine the effect of the NF1 mutation on bone fracture healing, the parameter values of the factors describing the aberrant cellular behavior of haploinsufficient cells were altered in a previously established model of bone regeneration [2]. Next, a large sensitivity analysis using a uniform design of 200 different parameter value combinations was conducted to determine the (relative) importance of the altered parameter values on the callus tissue fractions. An additional outcome “CI” (complication index) was defined such that a high CI value corresponds to a high degree of severity of CPT, i.e. the fracture healing is severely impaired.</p> <p><strong>Results and discussion</strong></p> <p>A non-union resembling a CPT phenotype was predicted by the computational model when the parameter values were altered. From the sensitivity analysis the following factors were found to be very influential for the CI value: the rate of cartilage formation, duration of fibroblast invasion and the rate of endochondral ossification. Interestingly, many combinations of altered parameter values resulted in a similar CI value although the composition and spatial distribution of the tissues within the fracture callus was different. Moreover, the computational model predicts a wide range (0.01-0.89) of CI values, corresponding to different degrees of severity by which the pseudarthrosis presents itself.</p> <p><strong>Conclusion</strong></p> <p>In summary, we can conclude that a slower endochondral ossification process, an increased invasion of fibroblastic cells and a reduced rate of cartilage formation are key elements for the development of a congenital pseudarthrosis in the computational model. Experimental research is necessary to verify this hypothesis.</p> <p><strong>References</strong></p> <p>1. Pannier S (2011) Congenital pseudarthrosis of the tibia. Orthopaedics & Traumatology-Surgery & Research 97: 750-761.</p> <p>2. Carlier A, Geris L, Gastel NV, Carmeliet G, Oosterwyck HV (2014) Oxygen as a critical determinant of bone fracture healing-A multiscale model. J Theor Biol 365C: 247-264. S0022-5193(14)00601-8 [pii];10.1016/j.jtbi.2014.10.012 [doi].</p> <p>Presentation made at the 21st Congress of the European Society of Biomechanics, Prague