Diptoindonesin G is a middle domain HSP90 modulator for cancer treatment

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (

Experimental animal models of post-traumatic osteoarthritis of the knee

Due to the complex and dynamic nature of osteoarthritis (OA) and post-traumatic osteoarthritis (PTOA), animal models have been used to investigate the progression and pathogenesis of the disease. Researchers have used different experimental models to study OA and PTOA. With an emphasis on the knee joint, this review will compare and contrast the existing body of knowledge from anterior cruciate ligament transection models, meniscectomy models, combination models, as well as impact models in large animals to see how tissues respond to these different approaches to induce experimental OA and PTOA. The tissues discussed will include articular cartilage and the meniscus, with a focus on morphological, mechanical and histological assessments. The goal of this review is to demonstrate the progressive nature of OA by indicating the strong correlation between progressive tissue degeneration, change of mechanical properties, and loss of biochemical integrity and to highlight key differences between the most commonly used experimental animal models

Mechanical viability of a thermoplastic elastomer hydrogel as a soft tissue replacement material

Hydrogels are a class of synthetic biomaterials composed of a polymer network that swells with water and as such they have both an elastic and viscous component making them ideal for soft tissue applications. This study characterizes the compressive, tensile, and shear properties of a thermoplastic elastomer (TPE) hydrogel and compares the results to published literature values for soft tissues such as articular cartilage, the knee meniscus, and intervertebral disc components. The results show the TPE hydrogel material is viscoelastic, strain rate dependent, has similar surface and bulk properties, displays minimal damping under dynamic load, and has tension-compression asymmetry. When compared to other soft tissues it has a comparable equilibrium compressive modulus of approximately 0.5 MPa and shear modulus of 0.2 MPa. With a tensile modulus of only 0.2 MPa though, the TPE hydrogel is inferior in tension to most collagen based soft tissues. Additional steps may be necessary to reinforce the hydrogel system and increase tensile modulus depending on the desired soft tissue application. It can be concluded that this material could be a viable option for soft tissue replacements

Nanostructure-Driven Replication of Soft Tissue Biomechanics in a Thermoplastic Elastomer Hydrogel

Synthesis of hydrogel networks capable of accurately replicating the biomechanical demands of musculoskeletal soft tissues continues to present a formidable materials science challenge. Current systems are hampered by combinations of limited moduli at biomechanically relevant strains, inefficiencies driven by undesirable hysteresis and permanent fatigue, and recovery dynamics too slow to accommodate rapid cycling prominent in most biomechanical loading profiles. Here, we report on a novel paradigm in hydrogel design based on prefabrication of an efficient nanoscale network architecture using the melt-state self-assembly of amphiphilic block copolymers. Rigorous characterization and mechanical testing reveal that swelling of these preformed networks produces hydrogels with physiologically relevant moduli and water compositions, negligible hysteresis, subsecond elastic recovery rates, and unprecedented resistance to fatigue over hundreds of thousands of compression cycles. Furthermore, by relying only on simple thermoplastic processing to form these nanostructured networks, the synthetic complexities common to most solution-based hydrogel fabrication strategies are completely avoided

Comparison of two models of post-traumatic osteoarthritis; temporal degradation of articular cartilage and menisci

The objective of this study was to compare longitudinal results from two models of combined anterior cruciate ligament (ACL) and meniscal injury. A modified ACL transection (mACLT) model and a traumatic impact (ACLF) model were used to create an ACL rupture and acute meniscal damage in a Flemish Giant animal model. The animals were euthanized at time points of 4, 8, or 12 weeks. The menisci were assessed for equilibrium and instantaneous compressive modulus, as well as glycosaminoglycan (GAG) coverage. The articular cartilage was mechanically assessed for thickness, matrix modulus, fiber modulus, and permeability. Articular cartilage GAG coverage, fissuring, tidemark integrity, and subchondral bone thickness were measured. Both models resulted in damage indicative of osteoarthritis, including decreased meniscal mechanics and GAG coverage, increased permeability and fissuring of articular cartilage, and decreased GAG coverage. The mACLT model had an early and lasting effect on the menisci mechanics and GAG coverage, while cartilage damage was not significantly affected until 12 weeks. The ACLF model resulted in an earlier change of articular cartilage GAG coverage and fissuring in both the 8 and 12 week groups. The menisci were only significantly affected at the 12 week time point in the ACLF model. We concluded the progression of post traumatic osteoarthritis was dependent on injury modality: a point to be considered in future investigations. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:486–495, 2017

Dynamic compression of human and ovine meniscal tissue compared with a potential thermoplastic elastomer hydrogel replacement

Understanding how human meniscal tissue responds to loading regimes mimetic of daily life as well as how it compares to larger animal models is critical in the development of a functionally accurate synthetic surrogate. Seven human and eight ovine cadaveric meniscal specimens were regionally sectioned into cylinders 5 mm in diameter and 3 mm thick along with 10 polystyrene-b-polyethylene oxide block copolymer-based thermoplastic elastomer (TPE) hydrogels. Samples were compressed to 12% strain at 1 Hz for 5000 cycles, unloaded for 24 h, and then retested. No differences were found within each group between test one and test two. Human and ovine tissue exhibited no regional dependency (p \u3c 0.05). Human samples relaxed quicker than ovine tissue or the TPE hydrogel with modulus values at cycle 50 not significantly different from cycle 5000. Ovine menisci were found to be similar to human menisci in relaxation profile but had significantly higher modulus values (3.44 MPa instantaneous and 0.61 MPa after 5000 cycles compared with 1.97 and 0.11 MPa found for human tissue) and significantly different power law fit coefficients. The TPE hydrogel had an initial modulus of 0.58 MPa and experienced less than a 20% total relaxation over the 5000. Significant differences in the magnitude of compressive modulus between human and ovine menisci were observed, however the relaxation profiles were similar. Although statistically different than the native tissues, modulus values of the TPE hydrogel material were similar to those of the human and ovine menisci, making it a material worth further investigation for use as a synthetic replacement. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2722–2728, 2017

Corrigendum to “Effects of degeneration on the compressive and tensile properties of human meniscus”. (Journal of Biomechanics (2015) 48(8) (1407–1411), (S0021929015001323) (10.1016/j.jbiomech.2015.02.042))

The authors regret that there was a mistake in Eq. (1) on p. 1408. Eq. (1) should be modified to read [Formula presented] The authors would like to apologise for any inconvenience caused

Effects of degeneration on the compressive and tensile properties of human meniscus

Healthy menisci function within the joint to prevent the underlying articular cartilage from excessive loads. Understanding how mechanical properties of menisci change with degeneration can drive future therapeutic studies to prevent this degeneration. Thus, the goal of this study was to characterize both compressive and tensile moduli of human menisci with varying degrees of gross damage due to osteoarthritis (OA). Twenty four paired menisci were collected from total knee joint replacement patients and the menisci were graded on a scale from 0-4 according to level of gross meniscal degeneration with 0=normal and 4=full tissue maceration. Each meniscus was then sectioned into anterior and posterior regions and subjected to indentation relaxation tests. Samples were sliced into 1. mm thick strips, made into dumbbells using a custom punch, and pulled to failure. Significant decreases in instantaneous compressive modulus were seen in the lateral posterior region between grades 0 and 1 (36% decrease) and in the medial anterior regions between grades 1 and 2 (67% decrease) and 1 and 3 (72% decrease). Changes in equilibrium modulus where seen in the lateral anterior region between grades 1 and 2 (35% decrease), lateral posterior region between grades 0-2 (41% decrease), and medial anterior regions between grades 1 and 2 (59% decrease), 1 and 3 (67% decrease), 2 and 4 (54% decrease), and 3 and 4 (42% decrease). No significant changes were observed in tensile modulus across all regions and degenerative grades. The results of this study demonstrate the compressive moduli are affected even in early stages of gross degeneration, and continue to decrease with increased deterioration. However, osteoarthritic menisci retain a tensile modulus similar to that of previously reported healthy menisci. This study highlights progressive changes in meniscal mechanical compressive integrity as level of gross tissue degradation increases, and thus, early interventions should focus on restoring or preserving compressive integrity

A Hydrogel Meniscal Replacement: Knee Joint Pressure and Distribution in an Ovine Model Compared to Native Tissue

Pressure distribution of the native ovine knee meniscus was compared to a medial meniscectomy and three treatment conditions including a suture reattachment of the native tissue, an allograft, and a novel thermoplastic elastomer hydrogel (TPE) construct. The objective of this study was to assess the efficacy of a novel TPE hydrogel construct at restoring joint pressure and distribution. Limbs were loaded in uniaxial compression at 45°, 60°, and 75° flexion and from 0 to 181 kg. The medial meniscectomy decreased contact area by approximately 50% and doubled the mean and maximum pressure reading for the medial hemijoint. No treatment condition tested within this study was able to fully restore medial joint contact area and pressures to the native condition. A decrease in lateral contact area and increase in pressures with the meniscectomy was also seen; and to some degree, all reattachment and replacement conditions including the novel TPE hydrogel replacement helped to restore lateral pressures. Although the TPE construct did not perform as well as hoped in the medial compartment, it performed as well as, if not better, than the other reattachment and replacement options in the lateral. Further work is necessary to determine the best anchoring and attachment methods