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What is the best treatment for lumbar disc herniations? For patients failing six weeks of conservative care, the current literature supports surgical intervention or prolonged conservative management as appropriate treatment options for lumbar radiculopathy in the setting of disc herniation. Surgical intervention may result in more rapid relief of symptoms and restoration of function. While surgery appears to provide more rapid relief, many patients will gradually get better with continued nonoperative management; thus, patient education and active participation in decision-making is vital.

The interaction of immune cells with biomaterials has been identified as a possible predictor of either the success or the failure of the implant. Among immune cells, macrophages have been found to contribute to both of these possible scenarios, based on their polarization profile. This proof-of-concept study aimed to investigate if it was possible to affect the response of macrophages to biomaterials, by the release of anti-inflammatory mediators. Towards this end, a collagen scaffold, integrated with poly(lactic-co-glycolic acid)—multistage silicon particles (MSV) composite microspheres (PLGA-MSV) releasing IL-4 was developed (PLGA-MSV/IL-4). Macrophages’ response to the scaffold was evaluated, both in vitro with rat bone-marrow derived macrophages, and in vivo in a rat subcutaneous pouch model. In vitro experiments revealed an overexpression of anti-inflammatory associated genes ( Il - 10, Mrc1, Arg1 ) at as soon as 48 h. The analysis of the cells that infiltrated the scaffold, revealed a prevalence of CD206 + macrophages at 24 h. Our strategy demonstrated that it is possible to tune the in vivo early response to biomaterials by the release of an anti-inflammatory cytokine, and that could contribute to accelerate the resolution of the inflammatory phase, benefiting a vast range of tissue engineering applications.

Purpose Some patients will experience post-operative back pain following lumbar discectomy, and the potential sources for that pain are poorly understood. One potential source is the vertebral endplates. The goal of this study was to document the changes that occur in lumbar endplates following discectomies, and to assess associations between endplate changes and clinical outcomes. Methods Changes in lumbar endplates and discs were assessed from X-rays, CT and MRI exams by comparing preoperative imaging with imaging obtained at yearly intervals up to 5 years. 260 endplates in 137 patients with single-level herniation and discectomy were analyzed. The geometry of osseous defects in the endplates was measured from the CT exams, and marrow and disc changes adjacent to endplates were assessed from the MRI exams. Clinical outcome assessments were collected at each time point. Descriptive statistics were used to describe endplate defect sizes, and logistic regression and analysis of variance were used to identify potential associations between endplate and vertebral body changes and clinical outcomes. Results Approximately 14 % of the endplates had osseous defects prior to surgery. After surgery, 24 % of inferior and 43 % of superior endplates had defects. Change occurred within the first year and remained relatively constant over the next few years. Disc signal intensity worsened and disc height decreased following surgery. New Modic changes were also observed. None of these changes were associated with having achieved a clinically significant improvement in outcome scores. The follow-up rates were low at the later time points and significant associations cannot be ruled out. Conclusions This study documents lesion characteristics in detail and supports that osseous defects in the endplates at the level of a lumbar discectomy may be a relatively common finding following surgery, along with disc height loss, loss of disc signal intensity, and Modic changes. The clinical significance of these imaging findings could not be conclusively determined in this study.

The effect of the mechanical micro-environment on spinal cord injury (SCI) and treatment effectiveness remains unclear. Currently, there are limited imaging methods that can directly assess the localized mechanical behavior of spinal cords in vivo. In this study, we apply new ultrasound elastography (USE) techniques to assess SCI in vivo at the site of the injury and at the time of one week post injury, in a rabbit animal model. Eleven rabbits underwent laminectomy procedures. Among them, spinal cords of five rabbits were injured during the procedure. The other six rabbits were used as control. Two neurological statuses were achieved: non-paralysis and paralysis. Ultrasound data were collected one week post-surgery and processed to compute strain ratios. Histologic analysis, mechanical testing, magnetic resonance imaging (MRI), computerized tomography and MRI diffusion tensor imaging (DTI) were performed to validate USE results. Strain ratios computed via USE were found to be significantly different in paralyzed versus non-paralyzed rabbits. The myelomalacia histologic score and spinal cord Young’s modulus evaluated in selected animals were in good qualitative agreement with USE assessment. It is feasible to use USE to assess changes in the spinal cord of the presented animal model. In the future, with more experimental data available, USE may provide new quantitative tools for improving SCI diagnosis and prognosis.

Bone morphogenetic protein-2 (BMP-2) has been demonstrated to be one of the most vital osteogenic factors for bone augmentation. However, its uncontrolled administration has been associated with catastrophic side effects, which compromised its clinical use. To overcome these limitations, we aimed at developing a safer controlled and sustained release of BMP-2, utilizing poly(lactic-co-glycolic acid)-multistage vector composite microspheres (PLGA-MSV). The loading and release of BMP-2 from PLGA-MSV and its osteogenic potential in vitro and in vivo was evaluated. BMP-2 in vitro release kinetics was assessed by ELISA assay. It was found that PLGA-MSV achieved a longer and sustained release of BMP-2. Cell cytotoxicity and differentiation were evaluated in vitro by MTT and alkaline phosphatase (ALP) activity assays, respectively, with rat mesenchymal stem cells. The MTT results confirmed that PLGA-MSVs were not toxic to cells. ALP test demonstrated that the bioactivity of BMP-2 released from the PLGA-MSV was preserved, as it allowed for the osteogenic differentiation of rat mesenchymal stem cells, in vitro. The biocompatible, biodegradable, and osteogenic PLGA-MSVs system could be an ideal candidate for the safe use of BMP-2 in orthopedic tissue engineering applications.

This article proposes a chondroitin sulfate‐based biomimetic scaffold that recapitulates the physicochemical features of the chondrogenic niche and retains the immunosuppressive potential of mesenchymal stem cells in vitro, either in response to a proinflammatory cytokine or in the presence of stimulated peripheral blood mononuclear cells. Costs associated with degenerative inflammatory conditions of articular cartilage are exponentially increasing in the aging population, and evidence shows a strong clinical need for innovative therapies. Stem cell‐based therapies represent a promising strategy for the treatment of innumerable diseases. Their regenerative potential is undeniable, and it has been widely exploited in many tissue‐engineering approaches, especially for bone and cartilage repair. Their immune‐modulatory capacities in particular make stem cell‐based therapeutics an attractive option for treating inflammatory diseases. However, because of their great plasticity, mesenchymal stem cells (MSCs) are susceptible to different external factors. Biomaterials capable of concurrently providing physical support to cells while acting as synthetic extracellular matrix have been established as a valuable strategy in cartilage repair. Here we propose a chondroitin sulfate‐based biomimetic scaffold that recapitulates the physicochemical features of the chondrogenic niche and retains MSC immunosuppressive potential in vitro, either in response to a proinflammatory cytokine or in the presence of stimulated peripheral blood mononuclear cells. In both cases, a significant increase in the production of molecules associated with immunosuppression (nitric oxide and prostaglandins), as well as in the expression of their inducible enzymes (iNos, Pges, Cox‐2, and Tgf‐β). When implanted subcutaneously in rats, our scaffold revealed a reduced infiltration of leukocytes at 24 hours, which correlated with a greater upregulation of genes involved in inflammatory cell apoptotic processes. In support of its effective use in tissue‐engineering applications of cartilage repair, the potential of the proposed platform to drive chondrogenic and osteogenic differentiation of MSC was also proven. Significance Recently, increasing clinical evidence has highlighted the important role of proinflammatory mediators and infiltrating inflammatory cell populations inducing chronic inflammation and diseases in damaged cartilage. This work should be of broad interest because it proposes an implantable biomimetic material, which holds the promise for a variety of medical conditions that necessitate the functional restoration of damaged cartilage tissue (such as trauma, diseases, deformities, or cancer).

In mammals, tissue regeneration is accomplished through a well-regulated, complex cascade of events. The disruption of the cellular and molecular processes involved in tissue healing might lead to scar formation. Most tissue engineering approaches have tried to improve the regenerative outcome following an injury, through the combination of biocompatible materials, stem cells and bioactive factors. However, implanted materials can cause further healing impairments due to the persistent inflammatory stimuli that trigger the onset of chronic inflammation. Here, it is described at the molecular, cellular and tissue level, the body response to a functionalized biomimetic collagen scaffold. The grafting of chondroitin sulfate on the surface of the scaffold is able to induce a pro-regenerative environment at the site of a subcutaneous implant. The early in situ recruitment, and sustained local retention of anti-inflammatory macrophages significantly reduced the pro-inflammatory environment and triggered a different healing cascade, ultimately leading to collagen fibril re-organization, blood vessel formation, and scaffold integration with the surrounding native tissue.

The inflammatory response following implantation of a biomaterial is one of the major regulatory aspects of the overall regenerative process. The progress of inflammation determines whether functional tissue is restored or if nonfunctional fibrotic tissue is formed. This delicate balance is directed by the activity of different cells. Among these, macrophages and their different phenotypes, the inflammatory M1 to anti-inflammatory M2, are considered key players in the process. Recent approaches exploit macrophage’s regenerative potential in tissue engineering. Here, we propose a collagen scaffold functionalized with chondroitin sulfate (CSCL), a glycosaminoglycan known to be able to tune inflammation. We studied CSCL effects on bone-marrow-derived macrophages in physiological, and lipopolysaccharides-inflamed, conditions in vitro. Our data demonstrate that CSCL is able to modulate macrophage phenotype by inhibiting the LPS/CD44/NF-kB cascade. As a consequence, an upregulation of anti-inflammatory markers (TGF-β, Arg, MRC1, and IL-10) was found concomitantly with a decrease in the expression of pro-inflammatory markers (iNOS, TNF-α, IL-1β, IL-12β). We then implanted CSCL subcutaneously in a rat model to test whether the same molecular mechanism could be maintained in an in vivo environment. In vivo data confirmed the in vitro studies. A significant reduction in the number of infiltrating cells around and within the implants was observed at 72 h, with a significant downregulation of pro-inflammatory genes expression. The present work provides indications regarding the immunomodulatory potential of molecules used for the development of biomimetic materials and suggests their use to direct macrophage immune modulation for tissue repair.

Introduction Mesenchymal stem cells (MSCs) hold great promise for regenerative therapies in the musculoskeletal system. Although MSCs from bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) have been extensively characterized, there is still debate as to the ideal source of MSCs for tissue-engineering applications in bone repair. Methods MSCs were isolated from cortical bone fragments (CBF-MSCs) obtained from patients undergoing laminectomy, selected by fluorescence-activated cell sorting analysis, and tested for their potential to undergo mesodermic differentiation. CBF-MSCs were then compared with BM-MSCs and AD-MSCs for their colony-forming unit capability and osteogenic potential in both normoxia and hypoxia. After 2 and 4 weeks in inducing media, differentiation was assessed qualitatively and quantitatively by the evaluation of alkaline phosphatase (ALP) expression and mineral deposition (Von Kossa staining). Transcriptional activity of osteoblastogenesis-associated genes ( Alp , RUNX2 , Spp1 , and Bglap ) was also analyzed. Results The cortical fraction of the bone contains a subset of cells positive for MSC-associated markers and capable of tri-lineage differentiation. The hypoxic conditions were generally more effective in inducing osteogenesis for the three cell lines. However, at 2 and 4 weeks, greater calcium deposition and ALP expression were observed in both hypoxic and normoxic conditions in CBF-MSCs compared with AD- and BM-MSCs. These functional observations were further corroborated by gene expression analysis, which showed a significant upregulation of Bglap , Alp , and Spp1 , with a 22.50 (±4.55)-, 46.56 (±7.4)-, 71.46 (±4.16)-fold increase compared with their uninduced counterparts. Conclusions This novel population of MSCs retains a greater biosynthetic activity in vitro , which was found increased in hypoxic conditions. The present study demonstrates that quantitative differences between MSCs retrieved from bone marrow, adipose, and the cortical portion of the bone with respect to their osteogenic potential exist and suggests the cortical bone as suitable candidate to use for orthopedic tissue engineering and regenerative medicine.

Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occur via astounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1–RUNX2 (8.23–19.74 fold), SPARC (18.67–55.44 fold), and SPP1 (46.09–90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics.