Incorporating strontium enriched amorphous calcium phosphate granules in collagen/collagen-magnesium-hydroxyapatite osteochondral scaffolds improves subchondral bone repair.

Osteochondral defect repair with a collagen/collagen-magnesium-hydroxyapatite (Col/Col-Mg-HAp) scaffold has demonstrated good clinical results. However, subchondral bone repair remained suboptimal, potentially leading to damage to the regenerated overlying neocartilage. This study aimed to improve the bone repair potential of this scaffold by incorporating newly developed strontium (Sr) ion enriched amorphous calcium phosphate (Sr-ACP) granules (100-150 µm). Sr concentration of Sr-ACP was determined with ICP-MS at 2.49 ± 0.04 wt%. Then 30 wt% ACP or Sr-ACP granules were integrated into the scaffold prototypes. The ACP or Sr-ACP granules were well embedded and distributed in the collagen matrix demonstrated by micro-CT and scanning electron microscopy/energy dispersive x-ray spectrometry. Good cytocompatibility of ACP/Sr-ACP granules and ACP/Sr-ACP enriched scaffolds was confirmed with in vitro cytotoxicity assays. An overall promising early tissue response and good biocompatibility of ACP and Sr-ACP enriched scaffolds were demonstrated in a subcutaneous mouse model. In a goat osteochondral defect model, significantly more bone was observed at 6 months with the treatment of Sr-ACP enriched scaffolds compared to scaffold-only, in particular in the weight-bearing femoral condyle subchondral bone defect. Overall, the incorporation of osteogenic Sr-ACP granules in Col/Col-Mg-HAp scaffolds showed to be a feasible and promising strategy to improve subchondral bone repair.

Modulating design parameters to drive cell invasion into hydrogels for osteochondral tissue formation.

Background: The use of acellular hydrogels to repair osteochondral defects requires cells to first invade the biomaterial and then to deposit extracellular matrix for tissue regeneration. Due to the diverse physicochemical properties of engineered hydrogels, the specific properties that allow or even improve the behaviour of cells are not yet clear. The aim of this study was to investigate the influence of various physicochemical properties of hydrogels on cell migration and related tissue formation using in vitro, ex vivo and in vivo models. Methods: Three hydrogel platforms were used in the study: Gelatine methacryloyl (GelMA) (5% wt), norbornene hyaluronic acid (norHA) (2% wt) and tyramine functionalised hyaluronic acid (THA) (2.5% wt). GelMA was modified to vary the degree of functionalisation (DoF 50% and 80%), norHA was used with varied degradability via a matrix metalloproteinase (MMP) degradable crosslinker and THA was used with the addition of collagen fibrils. The migration of human mesenchymal stromal cells (hMSC) in hydrogels was studied in vitro using a 3D spheroid migration assay over 48h. In addition, chondrocyte migration within and around hydrogels was investigated in an ex vivo bovine cartilage ring model (three weeks). Finally, tissue repair within osteochondral defects was studied in a semi-orthotopic in vivo mouse model (six weeks). Results: A lower DoF of GelMA did not affect cell migration in vitro (p â€‹= â€‹0.390) and led to a higher migration score ex vivo (p â€‹< â€‹0.001). The introduction of a MMP degradable crosslinker in norHA hydrogels did not improve cell infiltration in vitro or in vivo. The addition of collagen to THA resulted in greater hMSC migration in vitro (p â€‹= â€‹0.031) and ex vivo (p â€‹< â€‹0.001). Hydrogels that exhibited more cell migration in vitro or ex vivo also showed more tissue formation in the osteochondral defects in vivo, except for the norHA group. Whereas norHA with a degradable crosslinker did not improve cell migration in vitro or ex vivo, it did significantly increase tissue formation in vivo compared to the non-degradable crosslinker (p â€‹< â€‹0.001). Conclusion: The modification of hydrogels by adapting DoF, use of a degradable crosslinker or including fibrillar collagen can control and improve cell migration and tissue formation for osteochondral defect repair. This study also emphasizes the importance of performing both in vitro and in vivo testing of biomaterials, as, depending on the material, the results might be affected by the model used.The translational potential of this article: This article highlights the potential of using acellular hydrogels to repair osteochondral defects, which are common injuries in orthopaedics. The study provides a deeper understanding of how to modify the properties of hydrogels to control cell migration and tissue formation for osteochondral defect repair. The results of this article also highlight that the choice of the used laboratory model can affect the outcome. Testing hydrogels in different models is thus advised for successful translation of laboratory results to the clinical application.

Engineered biochemical cues of regenerative biomaterials to enhance endogenous stem/progenitor cells (ESPCs)-mediated articular cartilage repair.

As a highly specialized shock-absorbing connective tissue, articular cartilage (AC) has very limited self-repair capacity after traumatic injuries, posing a heavy socioeconomic burden. Common clinical therapies for small- to medium-size focal AC defects are well-developed endogenous repair and cell-based strategies, including microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), and matrix-induced ACI (MACI). However, these treatments frequently result in mechanically inferior fibrocartilage, low cost-effectiveness, donor site morbidity, and short-term durability. It prompts an urgent need for innovative approaches to pattern a pro-regenerative microenvironment and yield hyaline-like cartilage with similar biomechanical and biochemical properties as healthy native AC. Acellular regenerative biomaterials can create a favorable local environment for AC repair without causing relevant regulatory and scientific concerns from cell-based treatments. A deeper understanding of the mechanism of endogenous cartilage healing is furthering the (bio)design and application of these scaffolds. Currently, the utilization of regenerative biomaterials to magnify the repairing effect of joint-resident endogenous stem/progenitor cells (ESPCs) presents an evolving improvement for cartilage repair. This review starts by briefly summarizing the current understanding of endogenous AC repair and the vital roles of ESPCs and chemoattractants for cartilage regeneration. Then several intrinsic hurdles for regenerative biomaterials-based AC repair are discussed. The recent advances in novel (bio)design and application regarding regenerative biomaterials with favorable biochemical cues to provide an instructive extracellular microenvironment and to guide the ESPCs (e.g. adhesion, migration, proliferation, differentiation, matrix production, and remodeling) for cartilage repair are summarized. Finally, this review outlines the future directions of engineering the next-generation regenerative biomaterials toward ultimate clinical translation.

Effectiveness of BMP-2 and PDGF-BB Adsorption onto a Collagen/Collagen-Magnesium-Hydroxyapatite Scaffold in Weight-Bearing and Non-Weight-Bearing Osteochondral Defect Bone Repair: In Vitro, Ex Vivo and In Vivo Evaluation.

Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.

AKAP2 overexpression modulates growth plate chondrocyte functions through ERK1/2 signaling.

In our previous study, the mutation c.2645A > C (p. E882A) was found in the A-Kinase Anchoring Protein 2 (AKAP2) gene, which plays an important role in regulating the development of the skeletal system; however, the specific effect of AKAP2 on chondrocyte proliferation and differentiation and the potential mechanism are still not clear. In the present study, we investigated the effect of AKAP2 in vitro. We successfully isolated human growth plate chondrocytes (GPCs) from growth plate cartilage tissues and identified GPCs by aggrecan expression and flow cytometric analysis. AKAP2 overexpression significantly promoted GPC proliferation, enhanced GPC differentiation, and promoted extracellular matrix (ECM) synthesis, whereas AKAP2 silencing exerted the opposite effects on GPCs. AKAP2 overexpression increased, while AKAP2 silencing decreased, the protein levels of p-extracellular regulated protein kinases (ERK)1/2. More importantly, the promotive effects of AKAP2 overexpression on GPC proliferation, differentiation, and ECM synthesis were significantly reversed by the ERK1/2 signaling antagonist U0126, suggesting that AKAP2 enhances GPC functions through ERK1/2 signaling. In conclusion, we demonstrate AKAP2 overexpression-induced enhancement of GPC functions through ERK1/2 signaling. Considering the critical role of GPC functions in adolescent idiopathic scoliosis (AIS) pathogenesis, the application of AKAP2 targeting in AIS treatment should be investigated in future studies.

Full-Endoscopic Posterior Lumbar Interbody Fusion Via an Interlaminar Approach Versus Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Preliminary Retrospective Study.

OBJECTIVES: Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has been performed as a minimally invasive surgery for lumbar degenerative disease, but previous MIS-TLIF methods have shown limitations by their own characters. In this study, we developed a newly interbody fusion technique of full-endoscopic posterior lumbar interbody fusion (FE-PLIF) via an interlaminar approach, presented its preliminary clinical results in comparison with MIS-TLIF procedure. METHODS: This study retrospectively reviewed 52 patients who underwent FE-PLIF (n = 22) or MIS-TLIF (n = 30) surgery between October 2018 and February 2019. Patient demographics, intraoperative parameters, and perioperative complications were collated. Clinical and radiologic outcomes were evaluated at each follow-up for up to 12 months. RESULTS: FE-PLIF demonstrated a longer operation time, less blood loss, and shorter hospitalization duration than MIS-TLIF. The visual analog scale (VAS) score for leg pain in both groups and for back pain in FE-PLIF group significantly improved at 1 week, while the VAS score for back pain in MIS-TLIF group significantly improved at 3 months. No significant difference in the VAS and Oswestry disability index scores was found between the groups at 3 months and 12 months. Fusion rates of definite grades were not significantly different between the groups (73.3% vs. 70.0%, P > 0.05). All patients who suffered from cage subsidence or nonunion were asymptomatic and did not require revision surgery during the follow-up. CONCLUSIONS: The FE-PLIF interlaminar approach is a safe and effective interbody fusion technique with less surgical trauma and similar outcomes compared to MIS-TLIF. However, this technique still requires technical advancements to improve efficiency and reduce technical complexity.

The LncRNA H19/miR-1-3p/CCL2 axis modulates lipopolysaccharide (LPS) stimulation-induced normal human astrocyte proliferation and activation.

Reactive astrocyte proliferation post SCI (spinal cord injury) leads to the formation of glial scars, thus hindering axon regeneration and SCI repair, during which the activation of astrocytes plays a central role. This study attempted to identify the lncRNA-miRNA-mRNA network which exerts a critical effect on normal human astrocyte (NHA) activation and proliferation during SCI inflammation. Herein, lncRNA H19 expression was increased by LPS in NHAs, and H19 was positively correlated with CCL2. H19 silencing in NHAs significantly attenuated the promoting effects of LPS stimulation on NHA proliferation and activation as manifested by inhibited cell viability and DNA synthesis capacity, reduced NHA activation markers, and reduced inflammatory factor concentrations (CCL2, IL-6, and TNF-α). miR-1-3p directly bound to H19 and the CCL2 3'UTR. miR-1-3p overexpression also attenuated the promoting effects of LPS stimulation on NHA proliferation and activation. H19 relieved miR-1-3p-induced inhibition of CCL2 expression by acting as a ceRNA. The inhibition of miR-1-3p could significantly reverse the effects of H19 silencing on NHA proliferation and activation, suggesting that the H19/miR-1-3p axis regulates the proliferation and activation of NHAs via CCL2. In conclusion, lncRNA H19, miR-1-3p, and CCL2 form a lncRNA-miRNA-mRNA axis that modulates NHA proliferation and activation in vitro.

Incidence of Subsidence of Seven Intervertebral Devices in Anterior Cervical Discectomy and Fusion: A Network Meta-Analysis.

BACKGROUND: Subsidence is an incapacitating complication in anterior cervical discectomy and fusion (ACDF). However, the debate over which of the intervertebral devices is associated with lower incidence of subsidence remains to be settled. METHODS: Seven dominant techniques comprising cage with plate (CP), iliac bone graft with plate (IP), Zero-profile cage with screws (Zero-P), ROI-C cages with clips (ROI-C), polyether ether ketone cage alone (PCA), iliac crest autogenous graft (ICAG), and titanium cage alone (TCA) were examined. The incidences of subsidence in the different groups were calculated and compared. RESULTS: A total of 30 studies with 2264 patients were identified. Overall, the CP group presented the lowest incidence of subsidence, and its incidence was significantly lower than that in the Zero-P group, the PCA group, the ICAG group, and the TCA group (P < 0.05). The incidence of subsidence in the IP group was significantly lower than that in the PCA group, the ICAG group, and the TCA group (P < 0.05). In single-level ACDF, the CP group presented the lowest incidence of subsidence, and its incidence was significantly lower than that in the PCA group and the TCA group (P < 0.05). No difference was found between single-level and multilevel ACDF and the incidence of subsidence was higher in those undergoing single-level ACDF. CONCLUSIONS: CP and IP resulted in a lower rate of subsidence than cage alone or ICAG. Zero-P and ROI-C cages led to similar subsidence rates with plate. All types of intervertebral device can be applied to both single-level and multilevel ACDF with comparable subsidence rate.

Minimum 2-Year Efficacy of Percutaneous Endoscopic Lumbar Discectomy versus Microendoscopic Discectomy: A Meta-Analysis.

BACKGROUND: Minimally invasive surgery in the treatment of lumbar disc herniation has gained popularity in recent years, as 2 dominant techniques, percutaneous endoscopic lumbar discectomy (PELD) and microendoscopic discectomy (MED) obtained comparable short-term clinical outcomes. However, midterm and long-term efficacy and reoperative rate are still debated. METHODS: Electronic databases Web of Science, PubMed, Scopus, Cochrane Library, EMBASE, Ovid, and EBSCO were searched. STATA 14.0 was used for statistical analysis. Odds ratio (OR) and 95% confidence interval (CI) were pooled to quantify the strength of the statistical differences. RESULTS: Nine studies (468 patients in the PELD group and 516 patients in the MED group) with high methodologic quality met the selection criteria. No differences were found in leg pain visual analog scale score before surgery or at any follow-up time after surgery. PELD obtained better outcomes in low back pain visual analog scale score, Oswestry Disability Index score, and excellent and good ratio after 24 months postoperatively (OR = -0.856, 95% CI -1.488 to -0.224, P = 0.008; OR = -0.425, 95% CI -0.724 to -0.127, P = 0.005; OR = 3.034; 95% CI 1.254 to 7.343; P = 0.014) compared with MED. No difference was found within 24 months postoperatively. No significant differences were found in complication, recurrence, and reoperation rates within and after 2 years postoperatively. CONCLUSIONS: Both PELD and MED can offer relatively effective and safe treatment for low back pain and radiculopathy associated with a herniated disc. PELD could obtain better midterm and long-term clinical outcomes compared with MED.

Percutaneous Endoscopic Lumbar Discectomy for Lumbar Disc Herniation with Modic Changes via a Transforaminal Approach: A Retrospective Study.

BACKGROUND: The surgical selection for patients with lumbar disc herniation (LDH) with Modic changes (MCs) is still contentious. Percutaneous endoscopic lumbar discectomy via a transforaminal approach (TF-PELD) as a representative minimally invasive spine surgery technique for LDH has been standardized. However, its efficacy has not been thoroughly described in the patients with LDH with MCs. OBJECTIVES: The goal of this study was to assess the clinical outcomes of TF-PELD in the treatment of LDH and MCs. STUDY DESIGN: Retrospective study. SETTING: Inpatient surgery center. METHODS: From January 2015 to December 2016, 276 patients with LDH showing normal or MCs signals in their bone marrow in our hospital were enrolled in this retrospective study. All patients suffered low back and leg pain because of LDH and underwent the TF-PELD procedure. Clinical outcomes were assessed according to the Visual Analog Scale (VAS) for back pain and leg pain, Oswestry Disability Index (ODI) for functional status assessment, and modified MacNab criteria for patient satisfaction. RESULTS: A total of 182 patients showed normal intensity, 44 patients showed Modic type 1 signals, and 50 patients showed Modic type 2 signals before surgery. The postoperative VAS and ODI scores were significantly improved compared with those preoperatively among the groups. In the Modic type 1 and 2 signals groups, however, the postoperative VAS scores for back pain and ODI scores showed an upward trend with the follow-up time extending. The recurrence rates were 4.4%, 9.1%, and 8.0% in the normal, Modic type 1 and 2 signals groups, respectively. The recurrence rates and satisfaction rates showed no significant difference among the groups at the final follow-up. LIMITATIONS: This study has a small sample size and the follow-up period was too short. There is no comparison with other therapeutic options such as fusion surgery or the lack of any other treatment. CONCLUSIONS: TF-PELD is an option for treatment of patients with LDH even if the patients show MCs. However, the postoperative back pain and functional status have the trend of deterioration with the time extending in patients with MCs, especially in the Modic type 1 signals. KEY WORDS: Modic changes, Modic type 1, Modic type 2, transforaminal percutaneous endoscopic lumbar discectomy, lumbar disc herniation, back pain, recurrence, complication.

Full-Endoscopic Lumbar Discectomy for Lumbar Disc Herniation with Posterior Ring Apophysis Fracture: A Retrospective Study.

OBJECTIVE: The present retrospective study evaluated the clinical results of full-endoscopic lumbar discectomy (FELD) for the treatment of lumbar disc herniation (LDH) with lumbar posterior ring apophysis fracture (PRAF) using an interlaminar or a transforaminal approach at an inpatient surgery center. METHODS: Patients with single-level LDH with type III PRAF who had undergone FELD using an interlaminar or a transforaminal approach from January 2010 to December 2015 were enrolled. The general data recorded included sex, age, location, surgical approach, operative time, hospital stay, perioperative complications, and recurrence. The presence of mobile and immobile fragments was documented. The clinical outcomes were evaluated using a visual analog scale for low back and leg pain. The Oswestry Disability Index was used for the functional assessment and the modified MacNab criteria for patient satisfaction. RESULTS: FELD was performed successfully in all cases and no serious perioperative complications were observed. A mobile fragment of PRAS was present in 18 patients and an immobile fragment in 15 patients. Complications occurred in 2 of the 33 included patients; 1 dual tear (3.0%) and 1 transient dysesthesia (3.0%) that did not require further treatment. Recurrence developed in 1 patient (3.0%) and required reoperation. The visual analog scale and Oswestry Disability Index scores had significantly improved postoperatively at 3, 6, and 12 months and the final follow-up visit (P < 0.05). Using the modified MacNab criteria, an excellent or good rate of 93.4% was achieved. CONCLUSIONS: FELD is a safe and effective minimally invasive approach for the treatment of LDH with type III PRAF. Sufficient preparation and experience are required to achieve satisfactory results.