Integration of mechanotransduction concepts in bone tissue engineering

Mechanical stimulus has been identified for a long time as a key player in the adaptation of the musculo-skeletal tissues to their function. Mechanical loading is then an intrinsic variable to be considered when new developments are proposed in bone tissue engineering. By combining structural biomechanics and mechanotransduction aspects, a new paradigm is presented for bone tissue engineering. It is proposed that in vivo mechanical loading be used to increased bone formation in the scaffold instead of pre-seeding the scaffold with cells or delivering growth factors. In this article, we demonstrated the feasibility of this approach and compared it to the classical tissue engineering strategy. In particular, we showed that bone formation could be increased in the scaffold that underwent mechanical loading during an in vivo study in rats. A model of bone formation was then proposed to translate the in vivo results into a possible clinical application where the loading of the scaffold would be transmitted by the sharing of the load between an implant and the bone scaffold

Biomechanics and tissue engineering

Development of artificial scaffold for musculo-skeletal applications, especially in load-bearing situations, requires the consideration of biomechanical aspects for its integrity and its function. However, the biomechanical loading could also be used to favour tissue formation through mechano-transduction phenomena. Design of scaffold could take advantages of this intrinsic mechanical loading

Viscoelastic properties of soft tissues:application to knee ligaments and tendons

Ligaments play a central role in the stability of the knee. Due to the increase in sport activities of the young population, rupture of the anterior cruciate ligament (ACL) has become a frequent clinical problem. A surgical procedure replacing the deficient ligament is performed to restore the knee's initial stability. Although this surgical technique is widespread and well established, long term clinical results are inconsistent and the stability of the knee is not always restored, leading to premature arthrosis of the knee. This inconsistency of ACL replacement motivated the present study. "Optimal" ACL replacement only can be performed if the static and dynamic properties of the ligament are precisely known. In order to investigate these mechanical properties, an experimental set-up was developed to test human cruciate ligaments, as well as patellar tendon, which is commonly used for cruciate ligament replacement. Traction tests at different constant rates of elongation and stress relaxation tests were performed at controlled temperature (37°C) and humidity (100%). Results showed that cruciate ligaments and patellar tendons exhibit a non-linear elastic behavior in addition to a viscous behavior. The viscous behavior encompassed two phenomena: first a behavior where stress depended on strain rate (short term memory effects) and second a behavior where stress relaxed on a longer time scale (long term memory effects). In order to describe the different mechanical behaviors of the specimens in a general mechanical framework, a theoretical model was developed by simultaneously taking into account the non-linear elastic behavior, the short term memory effects and the long term memory effects. This proceeding satisfied the basic mechanical and thermodynamical requirements. The originality of the present model is based on the fact that the different mechanical behaviors are described in one framework allowing a compact description of the biomechanical properties of different soft tissues. The description of the short term memory effects is new in situations involving large deformations. The model is restricted by considering the specimens as isotropic, homogeneous and incompressible. The identification process of the different mechanical behaviors was facilitated with the proposed model. The non-linear elasticity was described with two parameters, the short term memory effects with one parameter and the long term memory effects with six parameters. No statistical differences were found between the parameters used for the anterior cruciate ligaments, the posterior cruciate ligaments and patellar tendons. The non-linear elastic behavior was implemented in a finite element code. The stress field in an ACL was calculated during a knee flexion and a tibial drawer test. The calculated stress field was inhomogeneous, with the highest stress in the anteriormedial part of the ACL. It was found that internal rotation of the knee generally increased the calculated stress in the ACL. These numerical results agree with in vitro studies given in the literature. The numerical results yielded a stress field in the ligament which was complementary to in vitro studies, where only the resultant ligament force can be measured. Several useful clinical conclusions can be drawn from the present biomechanical study. Diagnosis of an ACL rupture is generally performed by a contralateral comparison of antero-postero knee laxity (tibial drawer test) using a quasi-static load. However, diagnosis of an injured knee would be more accurate if the antero-postero load was dynamically applied to the knee: in this case, a knee with a rupture ACL would not show any effect, whereas a knee with an intact ACL would become stiffer with increasing the strain rate. In case of ACL replacement, the graft should be preconditioned in order to diminish the effects of stress relaxation. During the rehabilitation program after an ACL suture or replacement, flexion of the knee in an internal position should be omitted because internal rotation increases the stresses in the ligament

Biodegradable HEMA-based hydrogels with enhanced mechanical properties

Hydrogels are widely used in the biomedical field. Their main purposes are either to deliver biological active agents or to temporarily fill a defect until they degrade and are followed by new host tissue formation. However for this latter application, biodegradable hydrogels are usually not capable to sustain any significant load. The development of biodegradable hydrogels presenting load-bearing capabilities would open new possibilities to utilize this class of material in the biomedical field. In this work, an original formulation of biodegradable photo-crosslinked hydrogels based on hydroxyethyl methacrylate (HEMA) is presented. The hydrogels consist of short-length poly(2-hydroxyethyl methacrylate) (PHEMA) chains in a star shape structure, obtained by introducing a tetra-functional chain transfer agent in the backbone of the hydrogels. They are cross-linked with a biodegradable N,O-dimethacryloyl hydroxylamine (DMHA) molecule sensitive to hydrolytic cleavage. We characterized the degradation properties of these hydrogels submitted to mechanical loadings. We showed that the developed hydrogels undergo long-term degradation and specially meet the two essential requirements of a biodegradable hydrogel suitable for load bearing applications: enhanced mechanical properties and low molecular weight degradation products

Experimental method to characterize the strain dependent permeability of tissue engineering scaffolds

Permeability is an overarching mechanical parameter encompassing the effects of porosity, pore size, and interconnectivity of porous structures. This parameter directly influences transport of soluble particles and indirectly regulates fluid pressure and velocity in tissue engineering scaffolds. The permeability also contributes to the viscoelastic behavior of visco-porous material under loading through frictional drag mechanism. We propose a straightforward experimental method for permeability characterization of tissue engineering scaffolds. In the developed set-up a step-wise spacer was designed to facilitate measurement of the permeability under different compressive strains while maintaining similar experimental conditions during the successive measurements. As illustration of the method, we measured the permeability of scaffolds presenting different average pore sizes and subjected to different compression values. Results showed an exponential relationship between the permeability and the average pore size of the scaffolds. Furthermore, the trend of the permeability decrease with compressive strains was depending on pore sizes of the scaffolds. The permeability also appeared to play a role in relaxation behavior of the scaffolds

Improving hydrogels’ toughness by increasing the dissipative properties of their network

The weak mechanical performance and fragility of hydrogels limit their application as biomaterials for load bearing applications. The origin of this weakness has been explained by the low resistance to chains breakage composing the hydrogel and to the cracks propagation in the hydrogel submitted to loading conditions. These low resistance and crack propagation were in turn related to an insufficient energy dissipation mechanism in the hydrogel structure. The goal of this study is to evaluate the dissipation mechanism in covalently bonded hydrogels so that tougher hydrogels can be developed while keeping for the hydrogel a relatively high mechanical stiffness. By varying parameters such as cross-linker type or concentration as well as water ratio, the dissipative properties of HEMA-based hydrogels were investigated at large deformations. Different mechanisms such as special friction-like phenomena, nanoporosity, and hydrophobicity were proposed to explain the dissipative behavior of the tested hydrogels. Based on this analysis, it was possible to develop hydrogels with increased toughness properties