A cartilage growth mixture model for infinitesimal strains: solutions of boundary-value problems related to in vitro growth experiments

A cartilage growth mixture (CGM) model is linearized for infinitesimal elastic and growth strains. Parametric studies for equilibrium and nonequilibrium boundary-value problems representing the in vitro growth of cylindrical cartilage constructs are solved. The results show that the CGM model is capable of describing the main biomechanical features of cartilage growth. The solutions to the equilibrium problems reveal that tissue composition, constituent pre-stresses, and geometry depend on collagen remodeling activity, growth symmetry, and differential growth. Also, nonhomogeneous growth leads to nonhomogeneous tissue composition and constituent pre-stresses. The solution to the nonequilibrium problem reveals that the tissue is nearly in equilibrium at all time points. The results suggest that the CGM model may be used in the design of tissue engineered cartilage constructs for the repair of cartilage defects; for example, to predict how dynamic mechanical loading affects the development of nonuniform properties during in vitro growth. Furthermore, the results lay the foundation for future analyses with nonlinear models that are needed to develop realistic models of cartilage growth

Modeling the collagen fibril network of biological tissues as a nonlinearly elastic material using a continuous volume fraction distribution function

Despite distinct mechanical functions, biological soft tissues have a common microstructure in which a ground matrix is reinforced by a collagen fibril network. The microstructural properties of the collagen network contribute to continuum mechanical tissue properties that are strongly anisotropic with tensile-compressive asymmetry. In this study, a novel approach based on a continuous distribution of collagen fibril volume fractions is developed to model fibril reinforced soft tissues as nonlinearly elastic and anisotropic material. Compared with other approaches that use a normalized number of fibrils for the definition of the distribution function, this representation is based on a distribution parameter (i.e. volume fraction) that is commonly measured experimentally while also incorporating pre-stress of the collagen fibril network in a tissue natural configuration. After motivating the form of the collagen strain energy function, examples are provided for two volume fraction distribution functions. Consequently, collagen second-Piola Kirchhoff stress and elasticity tensors are derived, first in general form and then specifically for a model that may be used for immature bovine articular cartilage. It is shown that the proposed strain energy is a convex function of the deformation gradient tensor and, thus, is suitable for the formation of a polyconvex tissue strain energy function

Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration.

BackgroundOne potential mechanism for early superficial cartilage wear in normal joints is alteration of the lubricant content and quality of synovial fluid. The purpose of this study was to determine if the concentration and quality of the lubricant, hyaluronan, in synovial fluid: (1) was similar in left and right knees; (2) exhibited similar age-associated trends, whether collected postmortem or antemortem; and (3) varied with age and grade of joint degeneration.MethodsHuman synovial fluid of donors (23-91 years) without osteoarthritis was analyzed for the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5-7 MDa, 1-2.5 MDa, 0.5-1 MDa, and 0.03-0.5 MDa. Similarity of data between left and right knees was assessed by reduced major axis regression, paired t-test, and Bland-Altman analysis. The effect of antemortem versus postmortem collection on biochemical properties was assessed for age-matched samples by unpaired t-test. The relationships between age, joint grade, and each biochemical component were assessed by regression analysis.ResultsJoint grade and the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5-7 MDa, 1-2.5 MDa, and 0.5-1 MDa in human synovial fluid showed good agreement between left and right knees and were similar between age-matched patient and cadaver knee joints. There was an age-associated decrease in overall joint grade (-15 %/decade) and concentrations of hyaluronan (-10.5 %/decade), and hyaluronan in the molecular weight ranges of 2.5-7 MDa (-9.4 %/decade), 1-2.5 MDa (-11.3 %/decade), 0.5-1 MDa (-12.5 %/decade), and 0.03-0.5 MDa (-13.0 %/decade). Hyaluronan concentration and quality was more strongly associated with age than with joint grade.ConclusionsThe age-related increase in cartilage wear in non-osteoarthritic joints may be related to the altered hyaluronan content and quality of synovial fluid

Syrbactin-class dual constitutive- and immuno-proteasome inhibitor TIR-199 impedes myeloma-mediated bone degeneration in vivo

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics

The Impact of Biomechanics in Tissue Engineering and Regenerative Medicine

Biomechanical factors profoundly influence the processes of tissue growth, development, maintenance, degeneration, and repair. Regenerative strategies to restore damaged or diseased tissues in vivo and create living tissue replacements in vitro have recently begun to harness advances in understanding of how cells and tissues sense and adapt to their mechanical environment. It is clear that biomechanical considerations will be fundamental to the successful development of clinical therapies based on principles of tissue engineering and regenerative medicine for a broad range of musculoskeletal, cardiovascular, craniofacial, skin, urinary, and neural tissues. Biomechanical stimuli may in fact hold the key to producing regenerated tissues with high strength and endurance. However, many challenges remain, particularly for tissues that function within complex and demanding mechanical environments in vivo. This paper reviews the present role and potential impact of experimental and computational biomechanics in engineering functional tissues using several illustrative examples of past successes and future grand challenges.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78125/1/ten.teb.2009.0340.pd

Mechanical evaluation of a tissue-engineered zone of calcification in a bone-hydrogel osteochondral construct

The objective of this study was to test the hypothesis that mechanical properties of artificial osteochondral constructs can be improved by a tissue-engineered zone of calcification at the bone-hydrogel interface. Experimental push-off tests were performed on osteochondral constructs with or without a tissue-engineered zone of calcification. In parallel, a numerical model of the osteochondral defect treatment was developed and validated against experimental results. .Experimental results showed that the shear strength at the bone-hydrogel interface increased by 100% with the tissue-engineered zone of calcification. Numerical predictions of the osteochondral defect treatment showed that the shear stress at the bone-hydrogel interface was reduced with the tissue-engineered zone of calcification. We conclude that a tissue-engineered zone of calcification in osteochondral constructs can provide two improvements. First, it increases the strength of the bone-hydrogel interface, and second, it reduces the stress at this interface

A Moufang loop, the exceptional Jordan algebra, and a cubic form in 27 variables

Let be the exceptional 27-dimensional Jordan algebra over . Its automorphism group is the Lie group F4 and this group is known to have a finite subgroup AL, where A is a self centralizing elementary abelian of order 27, L[congruent with]SL(3, 3), and L normalizes A. As an A-module, decomposes into a direct sum of 1-dimensional spaces x which afford the 27 distinct linear characters x[epsilon]A:=Hom(A, x). These spaces satisfy xy = xy. Let [omega] = e2[pi]i/3. There are a basis of of the form ex, for x[epsilon]A, and a function g:A x A-->3 such that (*) exey = (-2)e(x, y) [omega]g(x, y)exy, where c(x, y) = 0 if x and y are linearly dependent and c(x,y) = 1 otherwise. Identifying A with 33, we write x = (x1, x2, x3) and y = (y1, y2, y3). A function g which has the above properties is g(x,y) = -x1,x2,x3 - x3,y1,y2 + x2,x3,y1 + x1,y2,y3. The elements ex|x [epsilon] A generate the infinite commutative loop :={(-2)m[omega]nex|m[epsilon], n[epsilon]3, x[epsilon]A} under Jordan multiplication. The loop is not Moufang but has as quotient a Moufang loop of order 81 and exponent 3. Conversely, the loop may be constructed from scratch (using g) and used to define the Jordan algebra using the formula (*); this gives a new existence proof for a simple 27-dimensional Jordan algebra over fields of characteristic not 2 or 3 with a primitive cube root of unity (in characteristic 3, we get the group algebra of A). We discuss some finite groups associated to and the Lie groups F4() and 3E6() and compare the analogous situation with the loop 16, the Cayley numbers, and Lie groups G2() and D4(). We also get a new construction of the cubic form in 27 variables whose group is 3E6() and an easy and natural construction of the exotic 3-local subgroup 31+3+3:SL(3, 3).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28568/1/0000371.pd

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC

Evaluation of Autogenous Engineered Septal Cartilage Grafts in Rabbits: A Minimally Invasive Preclinical Model

Objectives. (1) Evaluate safety of autogenous engineered septal neocartilage grafts and (2) compare properties of implanted grafts versus controls. Study Design. Prospective, basic science. Setting. Research laboratory. Methods. Constructs were fabricated from septal cartilage and then cultured in vitro or implanted on the nasal dorsum as autogenous grafts for 30 or 60 days. Rabbits were monitored for local and systemic complications. Histological, biochemical, and biomechanical properties of constructs were evaluated. Results. No serious complications were observed. Implanted constructs contained more DNA (P<0.01) and less sGAG perDNA (P<0.05) when compared with in vitro controls. Confined compressive aggregate moduli were also higher in implanted constructs (P<0.05) and increased with longer in vivo incubation time (P<0.01). Implanted constructs displayed resorption rates of 20–45 percent. Calcium deposition in implanted constructs was observe. Conclusion. Autogenous engineered septal cartilage grafts were well tolerated. As seen in experiments with athymic mice, implanted constructs accumulated more DNA and less sGAG when compared with in vitro controls. Confined compressive aggregate moduli were higher in implanted constructs. Implanted constructs displayed resorption rates similar to previously published studies using autogenous implants of native cartilage