Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices


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Regenerative Medicine - 12222

Our current knowledge on OA as a severe human disorder for which there is no reliable cure to date has greatly increased from a basic point of view due to the availability of a variety of clinically relevant animal models, involving various, fine mechanisms that involve all the tissues in the joint. The identification of the processes and mediators underlying the initiation and progression of OA provides hope to establish adapted, novel clinical treatments with a strong emphasis on the use of MSCs and on tissue engineering approaches to deliver effective and safe therapeutic compounds in patients in a close future.

MC drafted in particular the Cell-matrix interface in OA section. LdG drafted in particular the Animal models of OA section. GF drafted in particular the Stem cells in OA section. PO drafted in particular the Bone in OA section. DP drafted in particular the High tibial osteotomy models section. PR drafted in particular the OA pathomechanisms section.

All of the authors read and approved the final manuscript. The authors declare that they have no conflicts of interest associated with this publication and that there has been no financial support for this work that may have influenced its outcome. National Center for Biotechnology Information , U. Journal List J Exp Orthop v. J Exp Orthop. Published online Sep Miguel Oliveira. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Jul 6; Accepted Sep 9. This article has been cited by other articles in PMC. Abstract Osteoarthritis OA is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure.

Open in a separate window. The bone in OA The chronological events controlling the pathology of OA are still debated but recent developments emphasized an early pathophysiological role of the subchondral bone. Cell-matrix interface in OA focus on the articular cartilage Cartilage degeneration is a hallmark of OA Malemud et al. Cartilage homeostasis. Natural and pathological OA cellular and metabolic balance. Animal models of OA The growing interest in both the factors triggering the development of OA and the therapeutic targets enabling more effective treatments has led to the introduction of a large number of animal models, depending on the many different aspects of human pathology.

Table 2 Invasive and non-invasive models. Invasive models Non-invasive models Advantages rapid induction, high reproducibility, readily available, widely described systems rapid induction, high reproducibility, low infection risk, long time frame of OA changes, allowing for early evaluation and intervention Limitations risk of infection, expertise needed, early changes often, undetectable because of rapid induction not readily available, expertise needed, scarce literature.

Table 3 Animal models. High tibial osteotomy models Preclinical large animal models of high tibial osteotomy HTO can be used to test different types of osteotomies and to evaluate the effect of lower limb alignment on the reconstructive therapy of cartilage lesions and on the development and progression of OA Allen et al. Table 4 Surgical anatomical parameters relevant for HTO in humans and sheep. Table 5 Probabilities of potential pitfalls among humans and sheep. Table 6 Stem cells for OA treatment: clinical evidence from randomized controlled trials. Tissue engineering in OA The ideal treatment for OA should control not only the symptoms but also slow down or prevent the degradation of the joint.

Conclusions Our current knowledge on OA as a severe human disorder for which there is no reliable cure to date has greatly increased from a basic point of view due to the availability of a variety of clinically relevant animal models, involving various, fine mechanisms that involve all the tissues in the joint.

Competing interests The authors declare that they have no conflicts of interest associated with this publication and that there has been no financial support for this work that may have influenced its outcome. Perfusion abnormalities in subchondral bone associated with marrow edema, osteoarthritis, and avascular necrosis.

Ann N Y Acad Sci. R-spondins are newly recognized players in osteoarthritis that regulate Wnt signaling in osteoblasts. Arthritis Rheum. Mobilization of bone marrow-derived mesenchymal stem cells into the injured tissues after intraarticular injection and their contribution to tissue regeneration. Knee Surg Sports Traumatol Arthrosc. The surgical anatomy of the stifle joint in sheep.

Vet Surg. Remodelling of subchondral bone in osteoarthritis: a histomorphometric study. J Clin Pathol. Signal transduction through chondrocyte integrin receptors induces matrix metalloproteinase synthesis and synergizes with interleukin Venous engorgement and intraosseous hypertension in osteoarthritis of the hip.

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Osteoarthritis: an update with relevance for clinical practice. Hypoxia and vitamin D differently contribute to leptin and dickkopf-related protein 2 production in human osteoarthritic subchondral bone osteoblasts. Arthritis Res Ther. Post-traumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. Eur J Nucl Med. Early radiographic features in patients with anterior cruciate ligament rupture. Ann Rheum Dis. Anatomy and physiology of the mineralized tissues: role in the pathogenesis of osteoarthrosis. Bone remodelling in osteoarthritis. Nat Rev Rheumatol.

Microfractures and microcracks in subchondral bone: are they relevant to osteoarthrosis? Rheum Dis Clin North Am. Bone marrow-derived cells and biophysical stimulation for talar osteochondral lesions: a randomized controlled study. Foot Ankle Int. The MSC: an injury drugstore. Cell Stem Cell. Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J Bone Miner Res. Intra-articular delivery of sinomenium encapsulated by chitosan microspheres and photo-crosslinked GelMA hydrogel ameliorates osteoarthritis by effectively regulating autophagy.

Non-invasive mouse models of post-traumatic osteoarthritis. Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production. A decreased subchondral trabecular bone tissue elastic modulus is associated with pre-arthritic cartilage damage. J Orthop Res. Regenerative approaches for the treatment of early OA. Evidence for a key role of leptin in osteoarthritis.

The tibial subchondral plate. A scanning electron microscopic study. J Bone Joint Surg Am. Noninvasive methods of measuring bone blood perfusion. Nat Med. Plain radiography or magnetic resonance imaging MRI : which is better in assessing outcome in clinical trials of disease-modifying osteoarthritis drugs? Summary of a debate held at the World Congress of Osteoarthritis Semin Arthritis Rheum. Beta 1 integrins mediate chondrocyte interaction with type I collagen, type II collagen, and fibronectin.

Exp Cell Res. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Stem cells in articular cartilage regeneration. J Orthop Surg Res. Fibronectin fragments and blocking antibodies to alpha2beta1 and alpha5beta1 integrins stimulate mitogen-activated protein kinase signaling and increase collagenase 3 matrix metalloproteinase 13 production by human articular chondrocytes.

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Crosstalk between cartilage and bone: when bone cytokines matter. Cytokine Growth Factor Rev. Collagen and non-collagenous protein content osteocalcin, sialoprotein, proteoglycan in the iliac crest bone and serum osteocalcin in women with and without hand osteoarthritis. Coll Relat Res. J Cell Physiol. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Inflammation in osteoarthritis. Curr Opin Rheumatol. A review of translational animal models for knee osteoarthritis. Subchondral bone in osteoarthritis. Calcif Tissue Int. Human adult chondrocytes express hepatocyte growth factor HGF isoforms but not HgF: potential implication of osteoblasts on the presence of HGF in cartilage.

The pericellular matrix as a transducer of biomechanical and biochemical signals in articular cartilage. Proteoglycans and more -- from molecules to biology. Int J Exp Path. The role of the cartilage matrix in osteoarthritis. Can one generate stable hyaline cartilage from adult mesenchymal stem cells? A developmental approach. J Tissue Eng Regen Med. Osteoblast-like cells from human subchondral osteoarthritic bone demonstrate an alterd phenotype in vitro: possible role in subchondral bone sclerosis.

Similarities and discrepancies in subchondral bone structure in two differently induced canine models of osteoarthritis. Radiological assessment of osteo-arthrosis. Articular chondrocytes express connexion 43 hemichannels and P2 receptors - a putative mechanoreceptor complex involving the primary cilium?

J Anat. Hyaluronan receptor-directed assembly of chondrocyte pericellular matrix. J Cell Biol. In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae.

Orthopedic Tissue Engineering Basic Science and Practice

Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Animal models of osteoarthritis: classification, update, and measurement of outcomes. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep. Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice.

Arch Oral Biol. Useful animal models for the research of osteoarthritis. Eur J Orthop Surg Traumatol. Tissue engineering. Subchondral and trabecular bone metabolism regulation in canine experimental knee osteoarthritis. The discoidin domain receptor DDR2 is a receptor for type X collagen.

Matrix Biol. High tibial osteotomy using polycaprolactone-tricalcium phosphate polymer wedge in a micro pig model. Post-traumatic osteoarthritis: from mouse models to clinical trials. Improvements in surgical technique of valgus high tibial osteotomy. Integrins and chondrocyte-matrix interactions in articular cartilage.

Osteoarthritis : a disease of the joint as an organ. Definition and classification of early osteoarthritis of the knee. Early osteoarthritis of the knee. Degradation of extracellular matrix in osteoarthritis : 4 fundamental questions. J Rheumatol. Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Abnormal cancellous bone collagen metabolism in osteoarthritis.

Basic Science

J Clin Invest. Estrogens, osteoarthritis and inflammation. Joint Bone Spine. Can altered production of interleukin-1beta, interleukin-6, transforming growth factor-beta and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients. Abnormal insulin-like growth factor 1 signaling in human osteoarthritic subchondral bone osteoblasts. Intra-articular administration of gelatin hydrogels incorporating rapamycin-micelles reduces the development of experimental osteoarthritis in a murine model. Animal models of osteoarthritis: comparisons and key considerations.

Vet Pathol. The consequences of meniscectomy. Localization of extracellular matrix receptors on the chondrocyte primary cilium. J Histochem Cytochem. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the horse. Genetically engineered mouse models reveal the importance of proteases as osteoarthritis drug targets. Curr Rheumatol Rep. The primary cilium as a dual sensor of mechanochemical signals in chondrocytes. Cell Mol Life Sci. Stem cell therapy in a caprine model of osteoarthritis.

Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Cartilage-specific knockout of the mechanosensory ion channel TRPV4 decreases age-related osteoarthritis. Sci Rep. Gellam gum: a new biomaterial for cartilage tissue engineering applications. J Biomed Mater Res A.

Protective effect of a new biomaterial against the development of experimental osteoarthritis lesions in rabbit: a pilot study evaluating the intra-articular injection of alginate-chitosan beads dispersed in an hydrogel. Alterations of the subchondral bone in osteochondral repair--translational data and clinical evidence. Eur Cell Mater. The preclinical sheep model of high tibial osteotomy relating basic science to the clinics: standards, techniques and pitfalls. Differences in fixation stability between spacer plate and plate fixator following high tibial osteotomy.

Gene delivery to cartilage defects using coagulated bone marrow aspirate. Gene Ther. What is the predictive value of MRI for the occurrence of knee replacement surgery in knee osteoarthritis? Adipose-derived mesenchymal stem cells for the treatment of articular cartilage: a systematic review on preclinical and clinical evidence.

Stem Cells Int. Gellan gum-based hydrogel bilayered scaffolds for osteochondral tissue engineering. Key Eng Mater. Osteochondral plate angiogenesis: a new treatment target in osteoarthritis. Chondrons extracted from canine tibial cartilage: preliminary report on their isolation and structure. Characterizing a novel and adjustable noninvasive murine joint loading model. A comparative anatomical study of the human knee and six animal species. NF-kappa B mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments.

J Immunol. Subchondral bone changes in patients with early degenerative joint disease. Role of mechanical factors in pathogenesis of primary osteoarthritis. Regenerative medicine in rheumatic disease-progress in tissue engineering. The chondrocyte primary cilium.

Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyapuronic acid: a randomized controlled trial. Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. A role for subchondral bone changes in the process of osteoarthritis: a micro-CT study of two canine models. BMC Musculoskelet Disord. J Biol Eng. Injectable perlecan domain 1-hyaluronan microgels potentiate the cartilage repair effect of BMP2 in a murine model of early osteoarthritis.

GA muscles were harvested and frozen sections were evaluated for engraftment using beta-galactosidase and antidystrophin antibody staining. Heterotopic ossification HO , also called fibrocytis ossificans, can be associated with blunt muscle injury in younger athletes. It can also occur as a complication of total hip replacement surgery. During the past two decades HO had been a serious problem for service members who receive high-energy penetrating injuries in blast-related amputations. The prophylaxis for HO that is typically offered includes radiation and anti-inflammatories.

However, in the military theater logistics and the traumatic condition of the patients dictates against those. It is being investigated as a potential orphan drug treatment for fibrodysplasia ossificans progressive, a rare genetic disorder. It has also been shown to reduce bone formation in traumatic models of HO. Palovarotene was given orally every other day for 14 days. The ability of Raman spectroscopy to detect early HO before radiographic changes occur was also tested.

Raman spectroscopy was able to detect markers of early HO formation before it becomes radiographically evident. During amputation debridement this could facilitate earlier diagnosis and treatment. Following joint replacement surgery, patients can develop asymptomatic peri-prosthetic osteolysis, which can lead to substantial bone loss prior to diagnosis. Revision surgery to treat osteolysis may be more challenging due to the extent of bone loss. Investigators set out to identify urinary biomarkers that differentiate total hip replacement patients who develop osteolysis from patients who do not.

Samples from h urine collections prior to surgery and annually thereafter were saved in 26 patients. At the first radiographic sign of osteolysis marker analysis was done on samples from the preoperative, first post-operative, and for the 6 years preceding diagnosis. Patients in the osteolysis and non-osteolysis groups were matched according to time post-surgery. They did not differ in the male to female ratio or age at surgery.

As bone ages the C-terminal telopeptide, another bone resorption marker, converts as the alpha form of aspartic acid present in CTx converts to the beta form beta-CTx. Interleukin-6 IL-6 , interleukin-8 IL-8 are markers of inflammation. The AUC was 1. Markers for collagen degradation and inflammation are potential non-invasive biomarkers to identify patients at risk for peri-implant osteolysis long before the emergence of radiographic signs.

The high accuracy of the pre-operative biomarker levels identify patient-specific factors leading to early osteolysis and the need to follow these patients more routinely. Discovery of biomarkers to identify peri-implant osteolysis before radiographic diagnosis. Magnetic resonance imaging MRI prepares the magnetization then acquires its signal after a short time delay, which is called the echo time that is typically ms. Short-T2 tissue includes mineralized tissue e. Significance of the results varied in different regions of the tissue analyzed. Investigators sought a balance between imaging speed and quantification errors using different imaging trajectories, thus facilitating the clinical use of quantitative UTE-MRI for cortical bone imaging.

Bovine cortical bone samples in formalin were scanned using 3 techniques designed to measure the magnetization transfer ratio MTR and MT modeling of water and collagen proton fractions and exchange rates 3. Collectively, these studies show that UTE-MRI may facilitate clinical determination of deep cartilage 2 and cortical bone 3 quality quantitatively. Fifteen years ago counseling obese patients with knee osteoarthritis would have focused on the impact of force on articular cartilage.

Metabolic syndrome MS is the combination of diabetes, hypertension, dyslipidemia, and obesity. The impact of MS on the cardiovascular system has been recognized for over a decade. The impact of obesity in the alteration of gut flora has recently gained attention. Gut microbiome dysbiosis is associated with increased systemic inflammation. One hallmark of this is macrophage migration to the synovium and accelerated knee OA. Oligofructose is a non-digestible prebiotic fiber that can restore the microbial community profile of an obese individual to that of a lean gut.

Investigators created an obese mouse model of trauma induce OA to test hypotheses that a proinflammatory shift in the gut microbiome causes more severe OA and that reversal of that shift with oral oligofructose would mitigate the effects of obesity on OA progression. They had a control weight gain population over twelve weeks to demonstrate that oligofructose does not prevent obesity in mice consuming a high-fat diet.

Also, oligofructose reversed the effect of obesity on the gut microbiome and the colon transcriptome. Oligofructose-supplemented obese mice have reduced systemic inflammation. There were four cytokines which are significantly increased in obese mice that were also significantly reduced in the oligofructose-supplemented group. This is matched by the reduction of obesity-associated macrophage migration to the synovium. Targeting the gut microbiome to treat the osteoarthritis of obesity.

JCI Insight. The gold standard for augmentation of bone defects is graft autograph taken at time of surgery. However, donor site complications detract from use of larger quantities of bone. The use of bone graft substitutes is often disappointing and graft failures can occur. Likewise, growth factor augmentation may have its complications and failures because of timing of release. Non-viral gene delivery vectors such as polyethylenimine, chitosan or nano-hydroxyapatite have been used to give controlled expression and release of growth factors such as bone morphogenetic protein-2 BMP-2 or vascular endothelial growth factor VEGF from plasmid DNA pDNA at a defect site by transfecting host mesenchymal stem cells MSCs.

Star-PLLs are non-viral gene delivery vectors incorporated into collagen scaffolds. Due to their unimolecular, modifiable design, they have the ability to complex nucleic acids with a high cargo loading capability. Histology revealed consistent and extensive deposition of highly mineralized osteoid in the gene activated scaffold group which was not observed in the scaffold alone group.

Trans ORS Paper There is significant variation in scar formation following tendon injury and repair. To study scar formation in animal models mechanical, biochemical, and cellular assessment requires destruction of the tendon in each of the stages of healing. Investigators have developed an ultrasound US -based metric to quantify scar tissue volume STV , allowing for a non-invasive in vivo characterization of tendon healing wherein image segmentation STV strongly correlates with traditional end-point metrics of gliding function.

A flexor FDL was transected and repaired in 12 week old Sa haploid better healers and wild type mice. At 7, 14, 20, and 28 days following flexor digitorum profundus tendon repair a MHz transducer probe was used to obtain frames of B-mode images in the sagittal plane were taken with 0.

For each stage of healing images were compared to histology at 14 and 28 days. Scar formation was quantified by measuring metatarsophalangeal MTP joint angle. Lower gliding resistance and higher MTP flexion angle indicate decreased scar and better gliding function. SCV correlated positively with decreased flexion and increased gliding resistance. Based on these findings there may be an increasing role for the use of US to asses therapeutic strategies aimed at scar reduction in tendon repair.

Cartilage tissue engineering constructs are evaluated based on molecular content and mechanical properties that change depending on the length of culture and tissue source. The assessment requires tissue destruction. To assess cartilage matrix development over time multiple constructs must be made.

Non-destructive near infrared NIR spectral data has been used to evaluate engineered cartilage grown with bovine chondrocytes. This investigation hypothesized that NIR spectroscopic data along with multivariate partial least square PLS analysis techniques could be used to predict the compositional and biomechanical properties of engineered cartilage. NIR spectral data for sulfated glycosaminoglycan sGAG content and total collagen as well as mechanical properties were collected from constructs at days 0, 14, 28, and For correlation, biochemical and mechanical testing was performed on constructs at 2, 4 and 6 weeks.

Porcine data were compared to previously published bovine data. There are differences between species as to the change in rate of synthesis first derivative for collagen and sGAG. PLS analysis of NIR spectral data predicted biochemical composition and dynamic moduli of porcine constructs with This non-destructive method to determine the composition and mechanical properties of cartilage could allow researchers and clinicians to monitor tissue engineered constructs in real time to determine the optimal time for implantation without sacrificing samples.

The importance of perivascular cells pericytes in their role as stem cells has drawn exponential attention over the past decade. Their role in forming new tissue as well as paracrine signaling is becoming far better understood 1. EVs are small membrane-enclosed particles released by cells.

Proliferation was determined by ethynyldeoxyuridine EdU incorporation. Once Edu is incorporated by the cell it can be conjugated with fluorescent azides. Inflammation was determined by gene expression of COX-2 and interleukins 1alpha, 1beta, 6, 8 and 17, NFkB nuclear translocation and phosphorylation of IkB kinase. In addition, a decreased nuclear translocation of NFkB-p65 subunit and phosphorylated p65 and decreased phosphorylation of IkB kinase were observed. Given different methods of extracting EVs, variation with tissue source, age of donor, and other factors clinical applications will require biochemical monitoring for consistency of chemical content and dose before consistent results can be appreciated.

CC chemokines are chemokines that have two cysteine-cysteine pairs that attach to each other in a fold of the protein near the amino terminus. CCL indicates the roles of these proteins as ligands which are associated with chemokine activity. That axis is typically associated with degradation. To identify mechanisms of cartilage healing in juveniles, investigators focused on chemokines for their effects on the migration of stem cells and progenitor cells wherein a cartilage laceration injury would heal. At 4 and 8 weeks postoperatively, histological evaluation was performed.

In a separate experiment they made osteochondral defects in 15 week old rabbits and filled them with gel or gel with CCL A third group had no fill. At 16 weeks postoperatively, the reparative tissues in CCL21 group were predominantly hyaline-like cartilage with histological scores significantly better than those of other groups. Macroscopic score was 2. Histological scores likewise progressed from 4. There was no difference in subchondral bone volumes. CCL21 possibly recruited chondrogenic progenitor cells from bone marrow resulting in the enhancement of cartilage repair in the rabbit.

This raises the possibility that the modulation of CCL21 can improve cartilage repair in the adults. Trans Orthop Res Sco. Paper Polarization is not simply macrophage activation but exclusive selection of a differentiation path among several possible options. The term polarization has been borrowed from immunology, which due to the diversity and volatility of macrophage phenotypes may not be quite appropriate 1. On the other hand M2 polarization leads to activated healing macrophages with suppressed production of pro-inflammatory cytokines. Hence it seems logical that the path to new bone formation in fracture healing would be more related to M2 macrophages.

Within minutes of a fracture, the inflammatory phase of fracture healing starts. Shortly after both macrophages and mesenchymal stem cells MSCs arrive in the surrounding tissue. Investigators wished to define if M1 macrophages and MSCs worked in concert to promote bone healing 2. They co-cultured undifferentiated M0, pro-inflammatory M1, and anti-inflammatory M2 macrophages with primary murine bone marrow derived MSCs in vitro to determine the cross-talk between polarized macrophages and MSCs and the effects on osteogenesis.

After 4 weeks of co-culture, MSCs grown with macrophages had enhanced bone mineralization compared to MSCs grown alone. Of note, M1 macrophages had the highest level of bone formation after 4 weeks of culture. M1 cells are very important in the early stages of fracture healing, as the M1 chemokines call in cells to mop up the dead cellular debris and begin healing. Also, if M1 cells were converted to M2 before 72 hours, optimal bone formation does not occur. In this case, the interactions between macrophages and bone marrow MSCs provide opportunities to optimize bone healing and other regenerative processes via modulation of the inflammatory response and MSC phenotype change.

This is in contrast to collaborative MSC signaling that affects surrounding cells 3. The clinical assessment of fracture healing can be a costly and possibly inaccurate process. While computerized 3D imaging has improved the reliability of healing assessment, current imaging assesses only mineral aspects of a process that involves many tissues in the evolution of repair that varies with age and location. There is evidence that ultrasound can detect early callus formation, but is limited to superficial assessment and results are highly dependent on operator expertise. Radiographic assessment remains the most commonly used technique, but does not take into account cartilage and non-mineralized osteoid that may be sufficient to allow weight bearing.

Investigators designed a two-part study to validate the use of impedance spectroscopy to monitor fracture healing, with stages of healing confirmed through histological evidence. Impedance spectroscopy measures impedance with varying voltages and frequencies, encompassing resistive and capacitive components due to the ionic environment and cell membranes, respectively. A comminuted fracture was created in a thawed cadaveric leg using a chisel, and fragments were fixed with pins and external fixation. Cartilage, trabecular bone, and a mixture of the two were inserted into the fracture gaps.

Measurements were taken with two stainless steel pins as electrodes 2. The heterogeneous mixture of cartilage and trabecular bone resulted in measurements that fell approximately halfway between the individual tissues.


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A metal plate across the fractures did not affect the measurements, with no effect from screws if electrodes are placed far from the screws. Calluses were measured with impedance spectroscopy and tissue composition was quantified with histomorphometry. The opposite relationships were found when comparing phase angle to these phases. In open procedures the development of micro- and nanofabrication implants that feature wireless capabilities have potential use for early detection of bone healing and fracture nonunion.

New opportunities for fracture healing detection: Impedance spectroscopy measurements correlate to tissue composition in fractures. Epub Jun 9. Following injury and repair, reducing the time of tendon to bone healing helps avoid cartilage deterioration and muscle atrophy that may be hard to recover. It normally requires less time for bone to bone to heal in contrast to tendon to bone.

The region of tendon healing ideally results in reformation of the original tendon, fibrocartilage, and bone. Very often, for many reasons, remodeling falls short of that goal. Low intensity pulsed ultrasound LIPUS has been studied in fracture healing, both animal and clinical studies.

It has also been studied in animals for effect on tendon to bone healing from the inflammatory phase to remodeling. It has been found that there may be increased cell permeability in the first week wherein the LIPUS would be adverse. Hence investigators hypothesized that LIPUS starting at week two would accelerate new bone formation and remodeling. LIPUS was adapted to a 1. Daily treatment times were 20 minutes. There were 18 controls. Histologically, the LIPUS group showed more advanced remodeling of the lamellar bone and marrow cavity than the control group.

This model is not the same as the more difficult issue of rotator cuff repair where the tissue damage and biological environment is not the same as surgically induced tendon to bone repair. However, the time has come to look at the role of LIPUS and other physical modalities in enhancing surgical repair.

The effect of low-intensity pulsed ultrasound on bone-tendon junction healing: Initiating after inflammation stage. Epub Feb The role of cellular and matrix architecture in by region and depth in articular cartilage and by composite structure and function in bone. These regional differences also vary when they are investigated in different joints and bones.

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The biomechanical, and functional characteristics of the Achilles tendon are closely related to its composition and microstructure. Although elastin has been found in varying proportions in other connective tissues, previous studies report that tendons contain very small quantities of elastin.

Similarly, a laser which was tuneable was set at nm to acquire the SHG signals from the collagen. The SHG signals were directly collected by a secondary detector at nm for transmitted lights. With 3D imaging processing and 2D and fast fourier transform and alignment analysis matrix and cellular relationships could be studied in detail. This anatomical structural knowledge may enrich the theory of mechanical and biological information transduction in tendon tissue to develop future imaging techniques investigating tendon pathology.

Three dimensional microstructural network of elastin, collagen, and cells in Achilles tendons. Epub May 2. One of the holy grails of orthopaedics is finding a way to preserve femoral head shape during recovery from osteonecrosis. Whether in a pediatric or older adult population treatment options are often met with femoral head collapse, bone loss, and deformity. Creeping substitution is not the mechanism of repair. Hence, efforts to decrease absorption and increase new bone formation would be potentially useful in preventing femoral head deformity.

Using an immature pig model of surgically imposed osteonecrosis systemically administered ibandronate decreased bone absorption and femoral head deformity 1. For the next step the same investigators used the same drugs in an immature pig osteonecrosis model to determine the effects of BMP-2 and IB on the mineral content and nanoindentation properties of the bone following ONFH.

No significant difference was found between the BMP and the normal group. Question: will this biological support prove effective in humans? It appeared to be an alternative to surgery or at least would delay joint replacement. However, several metanalyses led the Academy of Orthopaedic Surgeons to recommend against VS as a treatment for osteoarthritis. VS is still controversial. In the process they wanted to identify clinical demographic, anthropometric, knee effusion, patient global assessment, and WOMAC score and radiological OARSI grade, patello-femoral involvement factors associated with lack of response.

Predictors of response were investigated in univariate then in multivariate analysis. The baseline characteristics and treatment effectiveness were similar between the 2 HA groups and thus that data was pooled. This was an older group with a mean age At 6 months, patients Baseline pain intensity and functional impairment were not associated with VS response.

Others might have applied the term phenotype. One way or the other this article highlights the careful thought in prospectively recording that should be applied to musculoskeletal research. Years ago it was recognized that fracture callus was formed by cells derived from the surrounding muscle. It has been found that, regardless of the tissue muscle fat, etc. The first phase of any healing process is inflammation. Inflammation is inherently associated with the development of new vasculature. Research on this and other processes led to the discovery of Human Mesenchymal Stem Cells, hMSCs, first named as such over 25 years ago.

It was found that these cells could differentiate into a number of different mesodermal phenotypes in cell culture. The capacity to form skeletal tissue in vitro encouraged the use of hMSCs for the fabrication of tissue engineered skeletal repair tissue with subsequent transplantation to in vivo sites. Based on markers CD and smooth muscle actin additional research has shown that most, if not all, MSCs are derived from perivascular cells otherwise known as pericytes.

Beyond the role of providing stem cells for musculoskeletal repair a complete re-evaluation of the role and functions of MSCs in the body has been found. As a case in point, the skeleton is a preferred organ for cancer dissemination for various tumor malignancies. To date, most efforts to understand skeletal metastasis have investigated the invasive and digestive capability of disseminated tumor cells DTCs. Recent investigations have determined that role of MSCs extends beyond that function. As an example these cells may act as a gatekeeper for metastasis of melanoma into bone.

In research where allogenic MSCs are mixed with autologous chondrones and placed in chondral defects in the human knee it was determined that no allogenic DNA remained at one year. Investigators hypothesized that the role of the MSCs was to communicate to the chondrones messages associated with the tilling of the defects with chondrocytes 2. It has been suggested that the name of MSCs be changes to Medicinal Signaling Cells to more accurately reflect the fact that these cells seek sites of injury or disease and secrete immunomodulatory and trophic are more like therapeutic drugs.

It should be noted that there are currently almost clinical trials listed using the MSCs as listed on clinicaltrials. Rheumatoid arthritis RA and other autoimmune diseases are characterized by transient disease flares that are mediated by increased levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha TNF. Current drug therapies for RA include a variety of biologic protein drugs e. Tumor necrosis factor TNF is a pro-inflammatory cytokine that has been implicated in a number of autoimmune diseases.

A number of TNF inhibitors are currently available and form the major class of biologic drug therapies for arthritis. The chemokine CC ligand 2 Ccl2 gene is also known as macrophage chemoattractant protein-1 gene Mcp In response to TNF, stem cells rapidly express Ccl2. The expression of IL-6 had a similar decrease of upregulation relative wo WT.

Also, this opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases. Stem Cell Reports. Epub Apr Trauma, overuse, subacromial bony impingement, and cigarette smoking are known to be associated with tears. Although many rotator cuff tears are associated with injury, tears in the absence of trauma are common, particularly in older individuals.

Evidence for heritable predisposition to rotator cuff tears RCTs is growing. The TNC gene encodes tenascin. Tenascin is a glycoprotein responsible for some cell signaling, embryological development, and matrix protein associations. Its expression is upregulated in wound healing and with inflammation subsequent to mechanical and degradative stress. To investigate the role of TNC gene expression in rotator cuff tears 59 unrelated Caucasian individuals with surgically diagnosed full thickness RCTs cases were compared to 32 elderly Caucasian controls with intact rotator cuffs.

It remains to be seen if these and other SNPs are associated with less favorable results in rotator cuff tendon repair and progression. Epub Jun Normal force per area is often measured in Pascals grams per Meter 2. In lower limb joints ankle, hip, and knee it is pretty well known that force concentration is 2 to 5 megapascals MPa with a wider range for some activities.

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As a point of comparison, normal atmospheric pressure at sea level is kilopascals. So what about the upper limb? Over a decade ago investigators recognized that despite the fact that investigators have explored static joint contact stresses estimated in vitro in many joints and in a number of species, although only rarely in vivo. Reviewing the literature on contact forces in both upper and lower limb joints they found that, despite a number of widely varying techniques and spatial resolutions to measure these contact stresses, reported ranges of static peak normal stresses were relatively similar from joint to joint across species range of 0.

They also noted that evidence suggested some disorders of cartilage deterioration are associated with somewhat higher peak pressures ranging from MPa, but overlapping the range of normal pressures. This, in part, may be explained by some evidence suggesting static contact stresses per se do not predict cartilage responses, but rather temporal aspects of the contact stress history. Given the question of contact stress history a remarkable concept was put forth over 20 years ago.

The proposal that there is a range of load that can be applied across an individual joint in a given period without supraphysiologic overload or structural failure. On a graph with increased applied loads on the vertical axis and the frequency of loading on the horizontal axis there is a curvilinear line below which a person would be within the envelope of function.

Four factors together determine the envelope of function for a given joint including anatomic, kinematic, physiologic, and treatment factors. This theory of joint function can result in a more rational clinical approach to treating patients with knee injuries and other orthopaedic conditions. A good clinical examples in the case of scapholunate dissociation. Surgical repair appeared to restore most measures of contact mechanics to near normal values.

This was best stated by Dr. This pathway controls gene expression programs for cell proliferation, cell polarity and cell fate determination during embryonic development as well as tissue homeostasis in adult life. Manipulating the pathway is a promising target to augment musculoskeletal stem cell MSC osteogenesis during healing.

Systemic drug delivery has the potential for numerous unwanted side effects since untargeted tissue can adversely respond. Physical treatments offer the advantage of focal application which avoids, in part, systemic effects. A means of circumventing unwanted side effects of systemically delivered materials is the use of nanoparticles NPs for drug delivery.

Some NPs are more selectively taken up by cells in regions of edema and vascular extravasation, such as that seen in tumors or fracture healing. Other NPs may have proteins that have an affinity for a specific tissue. Furthermore, fracture healing was evaluated using X-ray. The significance of this work is the development of targeted NPs for fracture-specific delivery of small molecule drugs.

Staphylococcus aureus and Staphylococcus epidermidis are predominant causes of total joint infections. Investigators proposed that chemical grafting of bioactive polymers onto the surface of implants could prevent bacterial adhesion and colonization. Sulfonate groups SO3- can be bonded to poly 1-phenylethene polysterene to from poly sodium styrene sulfonate poly NaSS which can be covalently linked to titanium alloy Ti6Al4V by a radical grafting process. Previous in vitro reports show poly NaSS resists enzymatic degradation, is very stable in physiological environments, reduces bacterial adhesion and colonization, and is capable of generating new active sites for protein binding.

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Grafted and ungrafted control Ti6Al4V surfaces were absorbed with adhesive proteins, including fibronectin Fn , collagen type I Col I and fibrinogen Fg , to study the ability of poly NaSS to promote bone-implant binding and prevent bacteria adhesion in the presence of these molecules at the interface, both in vitro and in vivo.

MC3T3-E1 osteoblastic cells were seeded and cultured up to 28 days. Significant cytoplasmatic cell expansion was observed on Fn adsorbed surfaces. Col I led to increased attachment strength enhancing alkaline phosphatase production and calcium and phosphate concentrations. In vivo Osseointegration and Implant Stability: Ti6Al4V cylinder-shaped implants were grafted with poly NaSS and plasma sprayed with hydroxyapatite and press-fit at both the femoral and the lateral condyles of 5 month old New Zealand white rabbits.

Osseointegration was promoted on poly NaSS grafted implants and physiological stability was greater compared to ungrafted and HA-coated Ti6Al4V measured in periods up to 12 months. In vitro Bacterial Adhesion: S. Fn and Fg increased staphylococcal adhesion on ungrafted Ti6Al4V surfaces. This presents great potential to the biomedical field. Trans ORS Over the years it has been accepted that hypertrophic cartilage cells in the physis die and that the residual calcified cartilage lattice is the framework upon which perivascular osteoblasts make the primary spongiosa.

This decades old model acquired the additional concept of hypertrophic chondrocyte apoptosis wherein the programed death would result in the necessary matrix changes for progression of vascular invasion into the physis leaving behind expired chondrocytes. There has been a dramatic change in this concept. Transdifferentiation is the change of a cell phenotype by the same cell.

An example is a chondrocyte transdifferentiating into an osteoblasts or osteocyte 1. What cell signals could be responsible for this remarkable transition? SHP2 is a cytoplasmic protein tyrosine phosphatase required for most, if not all, receptor tyrosine kinases, cytokine receptors and extracellular matrix protein signaling. This allowed evaluation of phenotypic expression as well cell source in the region of the physis. With SRT eliminated from the cell in in the COL2a1 group the mutants exhibited a cartilage pathophenotype, including dwarfism, cartilaginous exostoses and chondrodysplasia with elongated growth plate cartilage.

Taken together, this suggests that SHP2 deletion in hypertrophic chondrocytes compromises their transdifferentiation into bone-forming osteoblasts. Sox 9 is a transcription factor associated with chondrogenesis. Sox 9 expressing cells can be found in the periosteum of long bones.

For decades it has been taught that endochondral ossification during fracture healing involves the formation of a cartilage template wherein vessels invade the cartilage to create the marrow space and deliver the osteoprogenitor cells that form the new bone while the chondrocytes undergo apoptosis. In a fracture healing study using similar mouse genetic technology it was found that chondrocytes are the primary, if not the sole source of osteoblasts during bone fracture healing, and that the chondrocytes provide the new osteochondral progenitor cells that populate the newly formed periosteum.

The investigators also found that there was a direct contribution of these new periosteal cells to fracture callus following a second injury. More investigations will be required to determine the mechanisms that control the fates of the chondrocytes in the physis and in fracture healing. There are a number of risk factors for anterior cruciate injury. Variations in muscle strength and proprioception have a particular effect on female athletes.

Another is increased levels of relaxin. There are conflicting reports regarding the role of osseous morphologic characteristics such as an increased tibial slope in anterior cruciate ligament ACL injury. Few studies have analyzed the role of a combination of osseous morphologic characteristics in a matched case control study. One study was designed to determine if there is an association of specific osseous morphologic characteristics and ACL injury in male college American-football players.

Ninety male college football players had a magnetic resonance imaging MRI for a knee injury between and Measured osseous morphologic characteristics included medial and lateral condylar width, medial and lateral plateau width, notch width, bicondylar width, notch width index, and medial and lateral tibial slopes Conditional logistic regression was used to analyze the data.

Multivariable analysis revealed that increased lateral tibial slope odds ratio, 1. This information might help to improve prevention strategies to lower ACL injury. J Bone Joint Surg Am. Digital tomosynthesis DTS is a radiologic imaging device that produces a multi-slice image of an object. In DTS the x-ray source and detector are moved together during exposure, rapidly producing sharply focused planes. DTS has been used in fracture healing and the detection of occult fractures. Investigators used a radiologic portion of the OARSI osteoarthritis scoring system to investigate the reproducibility of osteoarthritis component scores comparing tomosynthesis to plain radiographs, using CT as a standard.

The OA components were:. There were 10 possible points for each for a minimum and maximum score of 0 to CPPD calcifications present in CT were also visible with tomosynthesis, but not with conventional radiography. Value of tomosynthesis for lesion evaluation of small joints in osteoarthritic hands using the OARSI score.

Osteoarthritis Cartilage. Epub Jan In articular cartilage tissue engineering there are five aspects: mechanical adequacy of scaffolds, cell source, cell signaling delivery product or genes , appropriate anatomic shape, and construct homeostasis. Most cartilage tissue engineering is aimed at focal defects since resurfacing of an entire osteoarthritic articular surfaces is difficult in the face of cartilage degeneration that occurs in osteoarthritis.

The inflammatory environment of OA may inhibit chondrogenesis and induce degradation of both native and engineered cartilage. In this study adult stem cells were engineered in 22 mm hemispherical scaffolds fabricated from3D woven poly e-caprolactone PCL cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist IL-1Ra. The constructs were seeded with human adipose-derived stem cells ASCs.

The constructs were cultured in chondrogenic conditions for 28 d. Cartilage properties and uniform tissue growth occurred and their anatomic shape was maintained throughout culture. Advanced textile manufacturing combined with scaffold mediated gene delivery was used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy.

The clinical step will be to determine the potential to provide mechanical functionality immediately upon implantation attempting to replace a majority, if not the entire joint surface to restore function. The development this technologies and others like it is constrained by the regulatory environment that governs their deployment. Novel technologies can require a long and formidable process that may overwhelm the financial realities of health care economics. Adequate stratification and identification of patients and an altered approval process must occur before complex therapies can provide the economic benefit to make them viable.

Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Tissue engineering and regenerative approaches to improving the healing of large bone defects. Eur Cell Mater. Metabolic syndrome describes the inflammatory effect of the combination of hyperlipidemia, hypertension, diabetes, and obesity. Metabolic syndrome has been found to be important in the inflammatory process in cardiovascular disease and more recently in osteoarthritis. In the cases of osteoarthritis, some authors feel that obesity is the greatest factor, independent of any mechanical effect.

Obese patients with knee osteoarthritis can benefit from diets aimed at all four aspects of metabolic syndrome. There is a study that may give some insight as to why this occurs. In a study a full thickness trochlear cartilage defect was created in 12 week old mice. The filling of that defect was studied at intervals in a normal group of mice and a group on a high fat diet.

Macrophage phenotype was unaffected. The effect of a high fat diet on musculoskeletal stem cells chondrogenesis could be different in different strains of mice. Obesity has been reported to negatively influence the clinical results of cartilage repair procedures and the results for this strain of mice was a surprise. This research reflects on the likelihood that not all obese patients should be excluded from cartilage regenerative treatment. These results invite research into understanding the protective mechanisms of older grossly obese metabolic syndrome patients who have no clinical evidence of knee osteoarthritis.

A more practical tool would be to define easily determined phenotypes. Bisphosphonates can be divided into non-amino bisphosphonates and amino-bisphosphonates. Both attach to bone surface, Amino-bisphosphonates result in osteoclast apoptosis as they initiate bone absorption. One alternative to bisphosphonates is Odanacatib, an inhibitor of cathepsin-K seen in osteoclast function. This way bone resorption is reduced without hindering bone formation. However there are issues with non-skeletal side effects. A fully humanized monoclonal antibody denosumab has been developed and shown to specifically inhibit RANK-L and, therefore, inhibit osteoclast-mediated bone destruction.

Wherein bisphosphonates can be taken orally these other agents require injections. Teriparatide is a recombinant form of active amino acid sequence of parathyroid hormone. The daily subcutaneous dose increases bone formation. This is in contract to persistent high PTH levels that lead to bone absorption. Both are anabolic agents, likely avoiding long term fatigue issues. Abaloparatide is a parathyroid hormone-related protein PTHrP analog now in clinical trials.

It appears to associate more strongly with R G conformation of the parathyroid hormone type 1 receptor. Non-vertebral fracture was lower with abaloparatide vs placebo. Incidence of hypercalcemia was lower with abaloparatide 3. The relative significance in vertebral fracture reduction was greater than reduction of other fractures.

In a commentary Dr. Cappola points out that for now the oral amino-bsphosphnates have a long term benefit, low risk to benefit ratio and relatively, and lower costs relative to the anabolic agents. Not mentioned is failure of physicians to identify osteoporosis and institution of vitamin D, calcium, and falls assessment in vulnerable persons. With the birth or total joint arthroplasty came the birth of loosening. The initial assumption was that there was infection involved. However, in many cases there was no evidence of infection. Hence the term, aseptic loosening AL was born.

That included particle size, composition, and shape. Now the question arises, are these loosenings really aseptic and does it affect outcomes on revision. It is noteworthy that 7 to 15 percent of these cases are bacterial culture negative. Loosening that occurs in the absence of these criteria and where there is no biochemical clinical suspicion of infection are considered aseptic. The increased incidence of infection on revision joint replacement relative to primary has been ascribed to tissue environment rather than occult infection in the index procedure.

That thinking is now under the proverbial microscope. Due to biofilm organisms can lie undeterred in the tissues and implant of a loose prosthesis. Albeit these and other methods have detected long term infection in loosening that occurs after many years of implantation the joint surgeon is faced with an implant that does not appear to merit the staged procedures that are used in known infected implants. There are a number of questions relative to the delivery of antibiotics at the time of surgery. The picture is complicated by the presence of microbial-associated molecular patterns MAMPs wherein some are related to biofilms but others are from sterile surface contaminants and not associated with bacteria.

The role of MAMPs in prosthetic loosening results from the cascade of events following stimulation of toll like receptors or tumor necrosis factor mediated immune responses. The path to reduction of AL will be paved in registry studies looking at occult infection prophylaxis along with improved detection of infection agents during the course of revision.

It will be biofilm at Knee osteoarthritis therapies have relied heavily on pharmacologic interventions. All have potential complications and some have controversial benefit. None extend the life of the joint. It had been recognized that that people cope differently with their knee osteoarthritis. These persons have been referred to as copers.


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  • A number of studies have shown weight loss as low as 20 pounds can have a considerable effect on pain improvement. Also, what is in a diet can have a significant effect on metabolic syndrome obesity, diabetes, hypertension, and dyslipidemia. The program lasted 24 weeks. Change is biomarkers, weight, pain, and disability were measured along with BMI at the beginning and end of the program. There was insufficient data for cytokines but pain remained improve at one year and there was some weight gained at one year. These programs require fairly intense involvement of it attendees. It is hard to say if the improvement in pain and function will motivate the individuals to maintain their behavioral change.

    Should that occur this could become a disease modifying intervention that is safe and free of complications. Pain coping skills training and lifestyle behavioral weight management in patients with knee osteoarthritis: a randomized controlled study. As a point of contrast are Type I-III collagen molecules which are just over amino acids long and measure X 1.

    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices
    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices
    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices
    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices
    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices
    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices
    Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices Orthopedic Tissue Engineering: Basic Science and Practice: Basic Science and Practices

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