Fluid flow impacts endothelial-monocyte interactions in a model of vascular inflammatory fibrosis.

The aberrant vascular response associated with tendon injury results in circulating immune cell infiltration and a chronic inflammatory feedback loop leading to poor healing outcomes. Studying this dysregulated tendon repair response in human pathophysiology has been historically challenging due to the reliance on animal models. To address this, our group developed the human tendon-on-a-chip (hToC) to model cellular interactions in the injured tendon microenvironment; however, this model lacked the key element of physiological flow in the vascular compartment.

Discoidin Domain Receptor 1 impacts bone microarchitecture with aging in female mice.

Discoidin Domain Receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagen(s), including collagen type I. deletion in osteoblasts and chondrocytes has previously demonstrated the importance of this receptor in bone development. In this study, we examined the effect of DDR1 ablation on bone architecture and mechanics as a function of aging.

Human Tendon-on-a-Chip for Modeling the Myofibroblast Microenvironment in Peritendinous Fibrosis.

Understanding the myofibroblast microenvironment is critical to developing therapies for fibrotic diseases. Here the development of a novel human tendon-on-a-chip (hToC) is reported to model this crosstalk in peritendinous adhesions, which currently lacks biological therapies. The hToC facilitates cellular and paracrine interactions between a vascular component, which contains endothelial cells and monocytes, and a tissue hydrogel component that houses tendon cells and macrophages.

High-throughput micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy.

Background: Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome measures of erosive arthritis in complex joints. In the case of preclinical models, such as sexually dimorphic tumor necrosis factor transgenic (TNF-Tg) mice, disease severity is routinely quantified in the ankle through manual segmentation of the talus or small regions of adjacent bones primarily due to the ease in measurement.

Biomechanical Effects of Subtalar Joint Fusion and Medial Ligament Reconstruction in Simulated Progressive Collapsing Foot Deformity.

Background: The purpose of this study is to investigate the biomechanical effect of medial displacement calcaneal osteotomy (MDCO), subtalar joint fusion (SF), and medial ligament reconstruction (MLR: deltoid-spring ligament) in a severe flatfoot model. We hypothesized that (1) combination of MDCO and SF improves the tibiotalar and foot alignment in severe progressive collapsing foot deformity (PCFD) cadaver model. (2) However, if a residual valgus heel alignment remains after MCDO and SF, it can lead to increased medial ligament strain, foot malalignment, and tibiotalar valgus tilt, which will be mitigated by the addition of MLR.

Human tendon-on-a-chip for modeling vascular inflammatory fibrosis.

Understanding vascular inflammation and myofibroblast crosstalk is critical to developing therapies for fibrotic diseases. Here we report the development of a novel human Tendon-on-a-Chip (hToC) to model this crosstalk in peritendinous adhesions, a debilitating fibrotic condition affecting flexor tendon, which currently lacks biological therapies. The hToC enables cellular and paracrine interactions between a vascular compartment harboring endothelial cells and monocytes with a tissue hydrogel compartment containing tendon fibroblasts and macrophages.

Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how).

Several tendon and ligament animal models were presented at the 2022 Orthopaedic Research Society Tendon Section Conference held at the University of Pennsylvania, May 5 to 7, 2022. A key objective of the breakout sessions at this meeting was to develop guidelines for the field, including for preclinical tendon and ligament animal models. This review summarizes the perspectives of experts for eight surgical small and large animal models of rotator cuff tear, flexor tendon transection, anterior cruciate ligament tear, and Achilles tendon injury using the framework: "Why, Who, What, Where, When, and How" (5W1H).

Guidelines for ex vivo mechanical testing of tendon.

Tendons are critical for the biomechanical function of joints. Tendons connect muscles to bones and allow for the transmission of muscle forces to facilitate joint motion. Therefore, characterizing the tensile mechanical properties of tendons is important for the assessment of functional tendon health and efficacy of treatments for acute and chronic injuries.

Effects of Acetabular Screws on the Initial Stability of Porous Coated Acetabular Implants in Revision Total Hip Arthroplasty.

Introduction: Revision total hip arthroplasty in the setting of acetabular bone loss remains a challenging clinical entity. Deficiencies of the acetabular rim, walls, and/or columns may limit the bony surface area and initial acetabular construct stability necessary for osseointegration of cementless components. Press-fit acetabular components with supplemental acetabular screw fixation represent a common technique aimed to minimize implant micromotion and allow for definitive osseointegration.

PAI-1 mediates TGF-β1-induced myofibroblast activation in tenocytes via mTOR signaling.

Transforming growth factor-beta (TGF-β1) induces plasminogen activator inhibitor 1 (PAI-1) to effect fibrotic pathologies in several organs including tendon. Recent data implicated PAI-1 with inhibition of phosphatase and tensin homolog (PTEN) suggesting that PAI-1-induced adhesions involves phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling. Ergo, we investigated effects of TGF-β1, PAI-1, and mTOR signaling crosstalk on myofibroblast activation, senescence, and proliferation in primary flexor tenocytes from wild-type (WT) and PAI-1 knockout (KO) mice.

Role of the Mitochondrial Permeability Transition in Bone Metabolism and Aging.

The mitochondrial permeability transition pore (MPTP) and its positive regulator, cyclophilin D (CypD), play important pathophysiological roles in aging. In bone tissue, higher CypD expression and pore activity are found in aging; however, a causal relationship between CypD/MPTP and bone degeneration needs to be established. We previously reported that CypD expression and MPTP activity are downregulated during osteoblast (OB) differentiation and that manipulations in CypD expression affect OB differentiation and function.

Identification of Penicillin Binding Protein 4 (PBP4) Inhibitors.

Methicillin-resistant (MRSA) is a global healthcare concern. Such resistance has historically been attributed to the acquisition of (or ), which encodes an alternative penicillin binding protein, PBP2a, with low β-lactam affinity. However, recent studies have indicated that penicillin binding protein 4 (PBP4) is also a critical determinant of methicillin resistance, particularly among community-acquired MRSA strains.

Transcriptional regulation of cyclophilin D by BMP/Smad signaling and its role in osteogenic differentiation.

Cyclophilin D (CypD) promotes opening of the mitochondrial permeability transition pore (MPTP) which plays a key role in both cell physiology and pathology. It is, therefore, beneficial for cells to tightly regulate CypD and MPTP but little is known about such regulation. We have reported before that CypD is downregulated and MPTP deactivated during differentiation in various tissues.

Human Organ-on-a-Chip Microphysiological Systems to Model Musculoskeletal Pathologies and Accelerate Therapeutic Discovery.

Human Microphysiological Systems (hMPS), otherwise known as organ- and tissue-on-a-chip models, are an emerging technology with the potential to replace animal studies with models that emulate human physiology at basic levels. hMPS platforms are designed to overcome limitations of two-dimensional (2D) cell culture systems by mimicking 3D tissue organization and microenvironmental cues that are physiologically and clinically relevant. Unlike animal studies, hMPS models can be configured for high content or high throughput screening in preclinical drug development.

A high-throughput semi-automated bone segmentation workflow for murine hindpaw micro-CT datasets.

Introduction: Micro-computed tomography (μCT) is a valuable imaging modality for longitudinal quantification of bone volumes to identify disease or treatment effects for a broad range of conditions that affect bone health. Complex structures, such as the hindpaw with up to 31 distinct bones in mice, have considerable analytic potential, but quantification is often limited to a single bone volume metric due to the intensive effort of manual segmentation. Herein, we introduce a high-throughput, user-friendly, and semi-automated method for segmentation of murine hindpaw μCT datasets.

Cantilever Bending of Murine Femoral Necks.

Fractures in the femoral neck are a common occurrence in individuals with osteoporosis. Many mouse models have been developed to assess disease states and therapies, with biomechanical testing as a primary outcome measure. However, traditional biomechanical testing focuses on torsion or bending tests applied to the midshaft of the long bones.

Determination of best Raman spectroscopy spatial offsets for transcutaneous bone quality assessments in human hands.

Spatially offset Raman spectroscopy (SORS) is able to detect bone signal transcutaneously and could assist in predicting bone fracture risk. Criteria for optimal source-detector offsets for transcutaneous human measurements, however, are not well-established. Although larger offsets yield a higher percentage of bone signal, the absolute amount of bone signal decreases.

Cell Wall Biosynthesis Modulates Bone Invasion and Osteomyelitis Pathogenesis.

invasion of the osteocyte lacuno-canalicular network (OLCN) is a novel mechanism of bacterial persistence and immune evasion in chronic osteomyelitis. Previous work highlighted cell wall transpeptidase, penicillin binding protein 4 (PBP4), and surface adhesin, surface protein C (SasC), as critical factors for bacterial deformation and propagation through nanopores , representative of the confined canaliculi . Given these findings, we hypothesized that cell wall synthesis machinery and surface adhesins enable durotaxis- and haptotaxis-guided invasion of the OLCN, respectively.

Chondral Damage After Arthroscopic Repair Techniques for Acute Bony Bankart Lesions: A Biomechanical Study.

Background: Bony Bankart lesions can be encountered during treatment of shoulder instability. Current arthroscopic bony Bankart repair techniques involve intra-articular suture placement, but the effect of these repair techniques on the integrity of the humeral head articular surface warrants further investigation.

Purpose: To quantify the degree of humeral head articular cartilage damage secondary to current arthroscopic bony Bankart repair techniques in a cadaveric model.

A Biomechanical, Cadaveric Evaluation of Single- Versus Double-Row Repair Techniques on Stability of Bony Bankart Lesions.

Background: Previous studies comparing stability between single- and double-row arthroscopic bony Bankart repair techniques focused only on the measurements of tensile forces on the bony fragment without re-creating a more physiologic testing environment.

Purpose: To compare dynamic stability and displacement between single- and double-row arthroscopic repair techniques for acute bony Bankart lesions in a concavity-compression cadaveric model simulating physiologic conditions.

Study Design: Controlled laboratory study.

Improved prediction of femoral fracture toughness in mice by combining standard medical imaging with Raman spectroscopy.

Bone fragility and fracture risk are assessed by measuring the areal bone mineral density (aBMD) using dual-energy X-ray absorptiometry (DXA). While aBMD correlates with bone strength, it is a poor predictor of fragility fracture risk. Alternatively, fracture toughness assesses the bone's resistance to crack propagation and fracture, making it a suitable bone quality metric.

NF-κB activation persists into the remodeling phase of tendon healing and promotes myofibroblast survival.

Although inflammation is necessary during the early phases of tissue repair, persistent inflammation contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because inflammation mediated by nuclear factor κB (NF-κB) signaling is implicated in this process, we examined the spatial, temporal, and cell type-specific activation profile of canonical NF-κB signaling during tendon healing.