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Item Anisotropic Properties of Articular Cartilage in an Accelerated In Vitro Wear Test(Elsevier, 2020-09) Hossain, M. Jayed; Noori-Dokht, Hessam; Karnik, Sonali; Alyafei, Naomi; Joukar, Amin; Trippel, Stephen B.; Wagner, Diane R.; Mechanical and Energy Engineering, School of Engineering and TechnologyMany material properties of articular cartilage are anisotropic, particularly in the superficial zone where collagen fibers have a preferential direction. However, the anisotropy of cartilage wear had not been previously investigated. The objective of this study was to evaluate the anisotropy of cartilage material behavior in an in vitro wear test. The wear and coefficient of friction of bovine condylar cartilage were measured with loading in directions parallel (longitudinal) and orthogonal (transverse) to the collagen fiber orientation at the articular surface. An accelerated cartilage wear test was performed against a T316 stainless-steel plate in a solution of phosphate buffered saline with protease inhibitors. A constant load of 160 N was maintained for 14000 cycles of reciprocal sliding motion at 4 mm/s velocity and a travel distance of 18 mm in each direction. The contact pressure during the wear test was approximately 2 MPa, which is in the range of that reported in the human knee and hip joint. Wear was measured by biochemically quantifying the glycosaminoglycans (GAGs) and collagen that was released from the tissue during the wear test. Collagen damage was evaluated with collagen hybridizing peptide (CHP), while visualization of the tissue composition after the wear test was provided with histologic analysis. Results demonstrated that wear in the transverse direction released about twice as many GAGs than in the longitudinal direction, but that no significant differences were seen in the amount of collagen released from the specimens. Specimens worn in the transverse direction had a higher intensity of CHP stain than those worn in the longitudinal direction, suggesting more collagen damage from wear in the transverse direction. No anisotropy in friction was detected at any point in the wear test. Histologic and CHP images demonstrate that the GAG loss and collagen damage extended through much of the depth of the cartilage tissue, particularly for wear in the transverse direction. These results highlight distinct differences between cartilage wear and the wear of traditional engineering materials, and suggest that further study on cartilage wear is warranted. A potential clinical implication of these results is that orienting osteochondral grafts such that the direction of wear is aligned with the primary fiber direction at the articular surface may optimize the life of the graft.Item Chondroprotective effects of Salubrinal in a mouse model of osteoarthritis(The British Editorial Society of Bone & Joint Surgery, 2015-05) Hamamura, K.; Nishimura, A.; Iino, T.; Takigawa, S.; Sudo, A.; Yokota, H.; Department of Engineering Technology, School of Engineering and TechnologyOBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). METHODS: OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. RESULTS: Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. CONCLUSIONS: Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84-92.Item Connexins and pannexins in the skeleton: gap junctions, hemichannels and more(Springer, 2015-08) Plotkin, Lilian I.; Stains, Joseph P.; Department of Anatomy & Cell Biology, IU School of MedicineRegulation of bone homeostasis depends on the concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts, controlled by osteocytes, cells derived from osteoblasts surrounded by bone matrix. The control of differentiation, viability and function of bone cells relies on the presence of connexins. Connexin43 regulates the expression of genes required for osteoblast and osteoclast differentiation directly or by changing the levels of osteocytic genes, and connexin45 may oppose connexin43 actions in osteoblastic cells. Connexin37 is required for osteoclast differentiation and its deletion results in increased bone mass. Less is known on the role of connexins in cartilage, ligaments and tendons. Connexin43, connexin45, connexin32, connexin46 and connexin29 are expressed in chondrocytes, while connexin43 and connexin32 are expressed in ligaments and tendons. Similarly, although the expression of pannexin1, pannexin2 and pannexin3 has been demonstrated in bone and cartilage cells, their function in these tissues is not fully understood.Item Effects of Angular Resolution and b Value on Diffusion Tensor Imaging in Knee Joint(Sage, 2021) Zhao, Qi; Ridout, Rees P.; Shen, Jikai; Wang, Nian; Radiology and Imaging Sciences, School of MedicineObjective: To investigate the influences of the diffusion gradient directions (angular resolution) and the strength of the diffusion gradient (b value) on diffusion tensor imaging (DTI) metrics and tractography of various connective tissues in knee joint. Design: Two rat knee joints were scanned on a preclinical 9.4-T system using a 3-dimensional diffusion-weighted spin echo pulse sequence. One protocol with b value of 500, 1500, and 2500 s/mm2 were acquired separately using 43 diffusion gradient directions. The other protocol with b value of 1000 s/mm2 was performed using 147 diffusion gradient directions. The in-plane resolution was 45 µm isotropic. Fractional anisotropy (FA) and mean diffusivity (MD) were compared at different angular resolution. Tractography was quantitatively evaluated at different b values and angular resolutions in cartilage, ligament, meniscus, and growth plate. Results: The ligament showed higher FA value compared with growth plate and cartilage. The FA values were largely overestimated at the angular resolution of 6. Compared with FA, MD showed less sensitivity to the angular resolution. The fiber tracking was failed at low angular resolution (6 diffusion gradient directions) or high b value (2500 s/mm2). The quantitative measurements of tract length and track volume were strongly dependent on angular resolution and b value. Conclusions: To obtain consistent DTI outputs and tractography in knee joint, the scan may require a proper b value (ranging from 500 to 1500 s/mm2) and sufficient angular resolution (>14) with signal-to-noise ratio >10.Item Effects of Gabapentin and Pregabalin on Calcium Homeostasis: Implications for Physical Rehabilitation of Musculoskeletal Tissues(Springer, 2022) Reyes Fernandez, Perla C.; Wright, Christian S.; Warden, Stuart J.; Hum, Julia; Farach-Carson, Mary C.; Thompson, William R.; Physical Therapy, School of Health and Human SciencesPurpose of review: In this review, we discuss the mechanism of action of gabapentinoids and the potential consequences of long-term treatment with these drugs on the musculoskeletal system. Recent findings: Gabapentinoids, such as gabapentin (GBP) and pregabalin (PGB) were designed as antiepileptic reagents and are now commonly used as first-line treatment for neuropathic pain and increasingly prescribed off-label for other pain disorders such as migraines and back pain. GBP and PGB exert their analgesic actions by selectively binding the α2δ1 auxiliary subunit of voltage-sensitive calcium channels, thereby inhibiting channel function. Numerous tissues express the α2δ1 subunit where GBP and PGB can alter calcium-mediated signaling events. In tissues such as bone, muscle, and cartilage, α2δ1 has important roles in skeletal formation, mechanosensation, and normal tissue function/repair that may be affected by chronic use of gabapentinoids. Long-term use of gabapentinoids is associated with detrimental musculoskeletal outcomes, including increased fracture risk. Therefore, understanding potential complications is essential for clinicians to guide appropriate treatments.Item Factors influencing cartilage wear in an accelerated in vitro test: collagen fiber orientation, anatomic location, cartilage composition, and photo-chemical crosslinking(2018) Hossain, M. Jayed; Wagner, Diane; Jones, Alan; Holguin, NilssonArticular cartilage (AC) is a strong but flexible connective tissue that covers and protects the end of the long bones. Although cartilage has excellent friction and wear properties that allow smooth joint function during daily activities, these properties are not fully understood. Many material properties of cartilage are anisotropic and vary with anatomic location and the composition of the tissue, but whether this is also true for cartilage friction and wear has not been previously determined. Furthermore, cartilage disease and injury are major health concerns that affect millions of people, but there are few available treatments to prevent the progression of cartilage degeneration. Collagen crosslinking may be a potential treatment to reduce cartilage wear and slow or prevent the progression of cartilage disease. The objectives of this thesis were to investigate the relationships between the friction/wear characteristics of cartilage and the orientation of the preferred fiber direction, the anatomic location of the tissue, the composition of the tissue, and exogenous photochemical crosslinking. In the superficial zone, AC has preferential fiber direction which leads to anisotropic material behavior. Therefore, we hypothesized that AC will show anisotropic behavior between longitudinal and transverse direction in an accelerated, in vitro wear test on bovine cartilage in terms of friction and wear. This hypothesis was proven by the quantification of glycosaminoglycans released from the tissue during the wear test, which showed that more glycosaminoglycans were released when the wear direction was transverse to the direction of the fibers. However, the hydroxyproline released from the tissue during the wear test was not significantly different between the two directions, nor was the coefficient of friction. The material properties of AC can also vary with anatomic location, perhaps due to differences in how the tissue is loaded in vivo. We hypothesized that cartilage from a higher load bearing site will give better wear resistance than cartilage from lower load bearing regions. However, no differences in friction or wear were observed between the different anatomic locations on the bovine femoral condyles. The concentration of collagen, glycosaminoglycans, cells and water in the tissue was also quantified, but no significant differences in tissue composition were found among the locations that were tested. Although wear did not vary with anatomic location, variation in the wear measurements were relatively high. One potential source of variation is the composition of the cartilage. To determine whether cartilage composition influences friction and wear, a correlation analysis was conducted. An accelerated, in vitro wear test was conducted on cartilage from bovine femoral condyles, and the tissue adjacent to the wear test specimens was analyzed for collagen, glycosaminoglycan, cell, and water content. Because wear occurs on the cartilage surface, the superficial zone of the cartilage might play an important role in wear test. Therefore, composition of the adjacent cartilage was determined in both the superficial zone and the full thickness of the tissue. A significant negative correlation was found between wear and collagen content in the full thickness of the tissue, and between the initial coefficient of friction and the collagen content in the superficial zone. This correlation suggests that variation in the collagen content in the full thickness of the cartilage partially explains differences in amount of wear between specimens. The wear resistance of cartilage can be improved with exogenous crosslinking agents, but the use of photochemical crosslinking to improve wear resistance is not well understood. Two photochemical crosslinking protocols were analyzed to improve the wear resistance of the cartilage by using chloro-aluminum phthalocyanine tetrasulfonic acid (CASPc) and 670nm laser light. The cartilage treated with the two crosslinking protocols had lower wear than the non-treated group without changing the friction properties of the cartilage.Item An Improved Methodology to Evaluate Cell and Molecular Signals in the Reparative Callus During Fracture Healing(Sage, 2020-03) Kambrath, Anuradha Valiya; Williams, Justin N.; Sankar, Uma; Anatomy and Cell Biology, School of MedicineApproximately 5% to 10% of all bone fractures do not heal completely, contributing to significant patient suffering and medical costs. Even in healthy individuals, fracture healing is associated with significant downtime and loss of productivity. However, no pharmacological treatments are currently available to promote efficient bone healing. A better understanding of the underlying molecular mechanisms is crucial for developing novel therapies to hasten healing. The early reparative callus that forms around the site of bone injury is a fragile tissue consisting of shifting cell populations held together by loose connective tissue. The delicate callus is challenging to section and is vulnerable to disintegration during the harsh steps of immunostaining, namely, decalcification, deparaffinization, and antigen retrieval. Here, we describe an improved methodology for processing early-stage fracture calluses and immunofluorescence labeling of the sections to visualize the temporal (timing) and spatial (location) patterns of cellular and molecular events that regulate bone healing. This method has a short turnaround time from sample collection to microscopy as it does not require lengthy decalcification. It preserves the structural integrity of the fragile callus as the method does not entail deparaffinization or harsh methods of antigen retrieval. Our method can be adapted for high-throughput screening of drugs that promote efficacious bone healing.Item Laryngeal Reconstruction Using Tissue-Engineered Implants in Pigs: A Pilot Study(Wiley, 2021-10) Brookes, Sarah; Zhang, Lujuan; Puls, Theodore J.; Kincaid, John; Voytik-Harbin, Sherry; Halum, Stacey; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective/hypothesis: There are currently no treatments available that restore dynamic laryngeal function after hemilaryngectomy. We have shown that dynamic function can be restored post hemilaryngectomy in a rat model. Here, we report in a first of its kind, proof of concept study that this previously published technique is scalable to a porcine model. Study design: Animal study. Methods: Muscle and fat biopsies were taken from three Yucatan minipigs. Muscle progenitor cells (MPCs) and adipose stem cells (ASCs) were isolated and cultured for 3 weeks. The minipigs underwent a left laterovertical partial laryngectomy sparing the left arytenoid cartilage and transecting the recurrent laryngeal nerve. Each layer was replaced with a tissue-engineered implant: 1) an acellular mucosal layer composed of densified Type I oligomeric collagen, 2) a skeletal muscle layer composed of autologous MPCs and aligned oligomeric collagen differentiated and induced to express motor endplates (MEE), and 3) a cartilage layer composed of autologous ASCs and densified oligomeric collagen differentiated to cartilage. Healing was monitored at 2 and 4 weeks post-op, and at the 8 week study endpoint. Results: Animals demonstrated appropriate weight gain, no aspiration events, and audible phonation. Video laryngoscopy showed progressive healing with vascularization and re-epithelialization present at 4 weeks. On histology, there was no immune reaction to the implants and there was complete integration into host tissue with nerve and vascular ingrowth. Conclusions: This pilot study represents a first in which a transmural vertical partial laryngectomy was performed and successfully repaired with a customized, autologous stem cell-derived multi-layered tissue-engineered implant.Item Post-traumatic osteoarthritis: A review of pathogenic mechanisms and novel targets for mitigation(Elsevier, 2023-01-30) Dilley, Julian E.; Bello, Margaret Anne; Roman, Natoli; McKinley, Todd; Sankar, Uma; Orthopaedic Surgery, School of MedicinePost-traumatic osteoarthritis (PTOA) develops secondary to a joint injury and accounts for 12 % of all osteoarthritis. These injuries, often of the lower extremity joints, occur due to trauma or accidents related to athletic or military activities. They primarily affect younger individuals although PTOA can occur across the spectrum of age. Pain and functional disability caused by PTOA confer a heavy economic toll on patients, in addition to detrimentally affecting their quality of life. Both high energy injuries that cause articular surface fracture with or without subchondral bone disruption and low-energy injuries involving joint dislocations or ligamentous injury cause PTOA, albeit through different mechanisms. Regardless, chondrocyte death, mitochondrial dysfunction, reactive oxygen species production, subchondral bone remodeling, inflammation and cytokine release in the cartilage and synovium play integral roles in the pathogenesis of PTOA. Evolving surgical methods are focused on stabilizing articular surface and joint structure congruity. However, to date there are no disease modifying medical therapies against PTOA. Increased recent understanding of the pathogenesis of the subchondral bone and synovial inflammation as well as that of chondrocyte mitochondrial dysfunction and apoptosis have led to the investigation of new therapeutics targeting these mechanisms to prevent or delay PTOA. This review discusses new advances in our understanding of cellular mechanisms underlying PTOA, and therapeutic approaches that are potentially effective in reducing the self-propagating cycle of subchondral bone alterations, inflammation, and cartilage degradation. Within this context, we focus therapeutic options involving anti-inflammatory and anti-apoptotic candidates that could prevent PTOA.Item The Response of Condylar Cartilage Stimulated by a Small Defect in the Rat Mandible(1983) Deguchi, Toshio; Kafrawy, Abdel; Tomich, Charles E.; Barton, Paul; Standish, S. Miles; Garner, LaForrest D.This study investigated the response of the condylar cartilage subjected to a small bone defect as a local stimulus in the rat mandible, in order to clarify one of the mechanisms of condylar cartilage growth. Fourteen male Wistar albino rats weighing 200 to 260 gm were divided into two groups, with two animals in a pilot study and 12 animals in the experimental group. Five male Wistar albino rats weighing 400 to 540 gm were used in a third group, which provided a basis for comparisons with the experimental group. To evaluate bone growth changes of the rat mandible, a superimpositioning method of tracings of the left and the right mandibles was done using the molars, incisors, anterior and inferior borders of the mandible. A sliding micrometer was used to measure each distance between the posterior edge of mental foramen (MF) and the posterior border of condylar process (CP) or angular process (AP). In the pilot study, one of two animals showed a decreased angular process and an increased condylar process, and the results suggested that the decreased activity of the masseter, resulting from dissecting a part of the masseter, may play an important role in changing the size or the shape of the rat mandible. In the experimental study, the masseter was not dissected and the results indicated that a hole drilled at the condylar notch did not stimulate condylar growth enough to be measurable. The third group showed that there were minor asymmetries between the left and the right mandible in normal rats, ranging from 0.49 to .0297 mm. Therefore, a larger sample size would be needed to arrive at definite conclusions.