The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundam... more The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundamental role in providing the spine with its unique structural and biomechanical functions. The inner part of the IVD contains the nucleus pulposus (NP), a gel-like tissue characterized by a high content of type II collagen and proteoglycans, which is crucial for the disc’s load-bearing and shock-absorbing properties. With aging and IVD degeneration (IDD), the NP gradually loses its physiological characteristics, leading to low back pain and additional sequelae. In contrast to surrounding spinal tissues, the NP presents a distinctive embryonic development since it directly derives from the notochord. This review aims to explore the embryology of the NP, emphasizing the pivotal roles of key transcription factors, which guide the differentiation and maintenance of the NP cellular components from the notochord and surrounding sclerotome. Through an understanding of NP development, we sought to investigate the implications of the critical developmental aspects in IVD-related pathologies, such as IDD and the rare malignant chordomas. Moreover, this review discusses the therapeutic strategies targeting these pathways, including the novel regenerative approaches leveraging insights from NP development and embryology to potentially guide future treatments.
Cell transplantation is being actively explored as a regenerative therapy for discogenic back pai... more Cell transplantation is being actively explored as a regenerative therapy for discogenic back pain. This study explored the regenerative potential of Tie2 + nucleus pulposus progenitor cells (NPPCs) from intervertebral disc (IVD) tissues derived from young (<25 years of age) and old (>60 years of age) patient donors. We employed an optimized culture method to maintain Tie2 expression in NP cells from both donor categories. Our study revealed similar Tie2 positivity rates regardless of donor types following cell culture. Nevertheless, clear differences were also found, such as the emergence of significantly higher (3.6-fold) GD2 positivity and reduced (2.7-fold) proliferation potential for older donors compared to young sources. Our results suggest that, despite obtaining a high fraction of Tie2 + NP cells, cells from older donors were already commi ed to a more mature phenotype. These disparities translated into functional differences, influencing colony formation, extracellular matrix production, and in vivo regenerative potential. This study underscores the importance of considering age-related factors in NPPC-based therapies for disc degeneration. Further investigation into the genetic and epigenetic alterations of Tie2 + NP cells from older donors is crucial for refining regenerative strategies. These findings shed light on Tie2 + NPPCs as a promising cell source for IVD regeneration while emphasizing the need for comprehensive understanding and scalability considerations in culture methods for broader clinical applicability.
Low back pain (LBP) and neck pain predominate as the primary causes of disability. Cell-and plate... more Low back pain (LBP) and neck pain predominate as the primary causes of disability. Cell-and platelet-rich plasma (PRP) products are potential therapies with clinical trials and reviews promoting their efficacy. Nonetheless, they frequently disregard the clinical significance of reported improvements. In this systematic review, the effectuated improvements in pain, disability, quality of life (QoL), and radiographic images are comprehensively described and scored on their clinical significance. An electronic database literature search was conducted on July 2023 for inhuman assessment of cell or PRP products to alleviate discogenic pain. Papers were screened on quantitative pain, disability, QoL, radiographic improvements, and safety outcomes. Risk of bias was assessed through MINORS and Cochrane Source of Bias tools. Reported outcomes were obtained, calculated, and assessed to meet minimal clinically important difference (MCID) standards. From 7623 screened papers, a total of 80 articles met the eligibility criteria, presenting 68 specific studies. These presented at least 1974 treated patients. Overall, cell/PRP injections could alleviate pain and disability, resulting in MCID for pain and disability in up to a 2-year follow-up, similar to those observed in patients undergoing spinal fusion. Included trials predominantly presented high levels of bias, involved heterogeneous study designs, and only a minimal number of randomized controlled trials. Nonetheless, a clear clinically significant impact was observed for cell-and PRP-treated cohorts with overall good safety
Purpose To investigate the therapeutic potential of extracellular vesicles (EVs) derived from hum... more Purpose To investigate the therapeutic potential of extracellular vesicles (EVs) derived from human nucleus pulposus cells (NPCs), with a specific emphasis on Tie2-enhanced NPCs, compared to EVs derived from human bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a coccygeal intervertebral disc degeneration (IDD) rat model. Methods EVs were isolated from healthy human NPCs cultured under standard (NPC STD-EVs) and Tie2-enhancing (NPC Tie2+-EVs) conditions. EVs were characterized, and their potential was assessed in vitro on degenerative NPCs in terms of cell proliferation and senescence, with or without 10 ng/mL interleukin (IL)-1β. Thereafter, 16 Sprague-Dawley rats underwent annular puncture of three contiguous coccygeal discs to develop IDD. Phosphate-buffered saline, NPC STD-EVs, NPC Tie2+-EVs, or BM-MSC-derived EVs were injected into injured discs, and animals were followed for 12 weeks until sacrifice. Behavioral tests, radiographic disc height index (DHI) measurements, evaluation of pain biomarkers, and histological analyses were performed to assess the outcomes of injected EVs. Results NPC-derived EVs exhibited the typical exosomal morphology and were efficiently internalized by degenerative NPCs, enhancing cell proliferation, and reducing senescence. In vivo, a single injection of NPC-derived EVs preserved DHI, attenuated degenerative changes, and notably reduced mechanical hypersensitivity. MSC-derived EVs showed marginal improvements over sham controls across all measured outcomes. Conclusion Our results underscore the regenerative potential of young NPC-derived EVs, particularly NPC Tie2+-EVs, surpassing MSC-derived counterparts. These findings raise questions about the validity of MSCs as both EV sources and cellular therapeutics against IDD. The study emphasizes the critical influence of cell type, source, and culture conditions in EV-based therapeutics.
Augmented reality (AR) is becoming more common and slowly being integrated into the surgical fiel... more Augmented reality (AR) is becoming more common and slowly being integrated into the surgical field. With the continuous progression of navigation and visualization techniques, AR has great potential to improve surgical quality and safety. Nevertheless, the effects of AR on surgical outcomes and surgeons' well-being remains poorly studied. The present prospective controlled study aims to assess the effect of surgery assisted with AR smart glasses on adolescent idiopathic scoliosis (AIS) deformity correction outcomes and surgeon fatigue.-METHODS: AIS patients scheduled for surgical deformity correction were prospectively recruited and assigned to standard or AR-supported surgery, using lightweight AR smart glasses. The demographic and clinical features were recorded. The pre-and postoperative spinal features, operative time, and blood loss were recorded and compared. Finally, the participating surgeons were asked to complete a questionnaire (e.g., visual analog scale for fatigue) to compare the effects of AR on their well-being.-RESULTS: Our results have shown enhanced spinal deformity corrections with Cobb angle (L35.7 vs. L46.9), thoracic kyphosis (8.1 vs. 11.6), and vertebral rotation (L9.3 vs. L13.8) changes favoring AR-supported surgery. Moreover, AR resulted in significantly lower violation rates per patient (7.5% vs. 6.6%; P [ 0.023). Finally, the visual analog scale for fatigue scores consistently showed a significant reduction in fatigue (5.7 AE 1.7 vs. 3.3 AE 1.2; P < 0.001) and other fatigue classifiers for the surgeons after AR-supported surgery.-CONCLUSIONS: Our controlled study has highlighted the enhanced spinal correction rates in AR-supported surgery and also improved surgeons' well-being and fatigue. These results endorse the adaptation of AR techniques to support AIS surgical correction.
Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebra... more Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebral disc (IVD) degeneration. Although oxidative stress has been shown to contribute to IVD degeneration, the underlying mechanisms remain undetermined. This study aimed to unravel the role of superoxide dismutase 2 (SOD2) in IVD pathogenesis and target oxidative stress to limit IVD degeneration. SOD2 demonstrated a dynamic regulation in surgically excised human IVD tissues, with initial upregulation in moderate degeneration and downregulation in severely degenerated IVDs. Through a comprehensive set of in vitro and in vivo experiments, we found a suggestive association between excessive mitochondrial superoxide, cellular senescence, and matrix degradation in human and mouse IVD cells. We confirmed that aging and mechanical stress, established triggers for IVD degeneration, escalated mitochondrial superoxide levels in mouse models. Critically, chondrocyte-specific Sod2 deficiency accelerated age-related and mechanical stress-induced disc degeneration in mice, and could be attenuated by β-nicotinamide mononucleotide treatment. These revelations underscore the central role of SOD2 in IVD redox balance and unveil potential therapeutic avenues, making SOD2 and mitochondrial superoxide promising targets for effective LBP interventions.
Low back pain (LBP) is a pervasive global issue causing substantial disability and significant ec... more Low back pain (LBP) is a pervasive global issue causing substantial disability and significant economic burden. The primary etiological factor behind LBP is intervertebral disc (IVD) degeneration, initiated in early adolescence and potentially leading to multiple spinal pathologies. However, current treatments for discogenic LBP are mainly palliative or involve invasive surgery, lacking disease-modifying therapies. Regenerative strategies, including cell therapy, may offer promising avenues to address the underlying pathology of IVD degeneration. Preclinical studies and clinical trials have demonstrated the potential of intradiscal cell transplantation to alleviate disc degeneration and associated pain with an overall favorable safety profile. Nonetheless, clinical trials present challenges, such as varying patient inclusion criteria, lack of adequate control groups, and short follow-up periods, necessitating cautious interpretation of results. This narrative review aims to provide an overview of clinical trials published to date and discuss the progress and translational hurdles of cell-based therapies for IVD degeneration and discogenic pain.
Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a... more Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a non-surgical alternative. This systematic review and meta-analysis aims to assess the efficacy and safety of chemonucleolytic enzymes for LDH. The primary objective is to evaluate efficacy through "treatment success" (i.e., pain reduction) and severe adverse events (SAEs) rates. Additionally, differences in efficacy and safety trends among chemonucleolytic enzymes are explored. Following our PROSPERO registered protocol (CRD42023451546) and PRISMA guidelines, a systematic search of PubMed and Web of Science databases was conducted up to July 18, 2023. Inclusion criteria involved human LDH treatment with enzymatic chemonucleolysis reagents, assessing pain alleviation, imaging changes, and reporting on SAEs, with focus on allergic reactions. Quality assessment employed the Cochrane Source of Bias and MINORS tools. Meta-analysis utilized odds ratios (OR) with 95% confidence intervals (CI). Among 62 included studies (12,368 patients), chemonucleolysis demonstrated an 79% treatment success rate and significantly outperformed placebo controls (OR 3.35, 95% CI 2.41-4.65) and scored similar to surgical interventions (OR 0.65, 95% CI 0.20-2.10). SAEs occurred in 1.4% of cases, with slightly higher rates in chymopapain cohorts. No significant differences in "proceeding to surgery" rates were observed between chemonucleolysis and control cohorts. Limitations include dated and heterogeneous studies, emphasizing the need for higher-quality trials. Further optimization through careful patient selection and advances in therapy implementation may further enhance outcomes. The observed benefits call for wider clinical exploration and adoption. No funding was received for this review.
Abstract: The intervertebral disc (IVD) is the largest avascular organ of the human body and play... more Abstract: The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundamental role in providing the spine with its unique structural and biomechanical functions. The inner part of the IVD contains the nucleus pulposus (NP), a gel-like tissue characterized by a high content of type II collagen and proteoglycans, which is crucial for the disc’s load-bearing and shock-absorbing properties. With aging and IVD degeneration (IDD), the NP gradually loses its physiological characteristics, leading to low back pain and additional sequelae. In contrast to surrounding spinal tissues, the NP presents a distinctive embryonic development since it directly derives from the notochord. This review aims to explore the embryology of the NP, emphasizing the pivotal roles of key transcription factors, which guide the differentiation and maintenance of the NP cellular components from the notochord and surrounding sclerotome. Through an understanding of NP development, we sought to investigate the implications of the critical developmental aspects in IVD-related pathologies, such as IDD and the rare malignant chordomas. Moreover, this review discusses the therapeutic strategies targeting these pathways, including the novel regenerative approaches leveraging insights from NP development and embryology to potentially guide future treatments.
Cell transplantation is being actively explored as a regenerative therapy for discogenic back pai... more Cell transplantation is being actively explored as a regenerative therapy for discogenic back pain. This study explored the regenerative potential of Tie2 + nucleus pulposus progenitor cells (NPPCs) from intervertebral disc (IVD) tissues derived from young (<25 years of age) and old (>60 years of age) patient donors. We employed an optimized culture method to maintain Tie2 expression in NP cells from both donor categories. Our study revealed similar Tie2 positivity rates regardless of donor types following cell culture. Nevertheless, clear differences were also found, such as the emergence of significantly higher (3.6-fold) GD2 positivity and reduced (2.7-fold) proliferation potential for older donors compared to young sources. Our results suggest that, despite obtaining a high fraction of Tie2 + NP cells, cells from older donors were already commi ed to a more mature phenotype. These disparities translated into functional differences, influencing colony formation, extracellular matrix production, and in vivo regenerative potential. This study underscores the importance of considering age-related factors in NPPC-based therapies for disc degeneration. Further investigation into the genetic and epigenetic alterations of Tie2 + NP cells from older donors is crucial for refining regenerative strategies. These findings shed light on Tie2 + NPPCs as a promising cell source for IVD regeneration while emphasizing the need for comprehensive understanding and scalability considerations in culture methods for broader clinical applicability.
The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a... more The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a rapid decline during aging and intervertebral disc degeneration, and has thus sparked interest in its utilization as a regenerative agent against disc degeneration. However, the challenge of maintaining and expanding these progenitor cells in vitro has been a significant hurdle. In this study, we investigated the potential of laminin-511 to sustain Tie2+ NP progenitor cells in vitro. We isolated cells from human NP tissue (n = 5) and cultured them for 6 days on either standard (Non-coat) or iMatrix-511 (laminin-511 product)-coated (Lami-coat) dishes. We assessed these cells for their proliferative capacity, activation of Erk1/2 and Akt pathways, as well as the expression of cell surface markers such as Tie2, GD2, and CD24. To gauge their regenerative potential, we examined their extracellular matrix (ECM) production capacity (intracellular type II collagen (Col2) and proteoglycans (PG))...
The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a... more The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a rapid decline during aging and intervertebral disc degeneration, and has thus sparked interest in its utilization as a regenerative agent against disc degeneration. However, the chal- lenge of maintaining and expanding these progenitor cells in vitro has been a significant hurdle. In this study, we investigated the potential of laminin-511 to sustain Tie2+ NP progenitor cells in vitro. We isolated cells from human NP tissue (n = 5) and cultured them for 6 days on either standard (Non-coat) or iMatrix-511 (laminin-511 product)-coated (Lami-coat) dishes. We assessed these cells for their proliferative capacity, activation of Erk1/2 and Akt pathways, as well as the expression of cell surface markers such as Tie2, GD2, and CD24. To gauge their regenerative po- tential, we examined their extracellular matrix (ECM) production capacity (intracellular type II collagen (Col2) and proteoglycans (PG)) and their ability to form spherical colonies within methyl- cellulose hydrogels. Lami-coat significantly enhanced cell proliferation rates and increased Tie2 expression, resulting in a 7.9-fold increase in Tie2-expressing cell yields. Moreover, the overall pro- portion of cells positive for Tie2 also increased 2.7-fold. Notably, the Col2 positivity rate was signifi- cantly higher on laminin-coated plates (Non-coat: 10.24% (±1.7%) versus Lami-coat: 26.2% (±7.5%), p = 0.010), and the ability to form spherical colonies also showed a significant improvement (Non-coat: 40.7 (±8.8)/1000 cells versus Lami-coat: 70.53 (±18.0)/1000 cells, p = 0.016). These findings demon- strate that Lami-coat enhances the potential of NP cells, as indicated by improved colony formation and proliferative characteristics. This highlights the potential of laminin-coating in maintaining the NP progenitor cell phenotype in culture, thereby supporting their translation into prospective clinical cell-transplantation products.
Background: Rubinstein-Taybi syndrome (RTS) is a rare disorder with a range of congenital anomali... more Background: Rubinstein-Taybi syndrome (RTS) is a rare disorder with a range of congenital anomalies. Although 40% to 60% of patients with RTS have scoliotic deformities, few reports discuss the outcomes of correctional surgery and postoperative care. To raise awareness of the clinical features of RTS and surgical considerations, the authors report on the surgical treatment of a pediatric patient with RTS accompanied by scoliosis. Observations: A 14-year-old girl with RTS presented with low back pain associated with progressive scoliosis. Because of jaw hypoplasia, videolaryngoscopy-mediated intubation was chosen. A single-stage T4-L3 posterior corrective fusion with instrumentation was successfully performed. Physical and imaging findings were analyzed up to 2 years after correction. The main thoracic Cobb angle was corrected from 73° to 12° and maintained for 2 years after surgery. The patient's low back pain resolved. Lessons: Careful consideration of RTS-associated complications and preoperative planning, including the use of videolaryngoscopy-mediated intubation, anesthesia selection, and postoperative care, proved crucial. Scoliosis may appear in many variations in rare diseases such as RTS. Publication of case reports such as this one is needed to provide detailed information about strategies and considerations for correcting scoliotic deformities in patients with RTS.
International Journal of Molecular Sciences, Apr 29, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
North American Spine Society Journal (nassj), Mar 1, 2023
Background: Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain ... more Background: Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain (LBP) and despite a prominent prevalence, present treatment options remain inadequate for a large portion of LBP patients. New developments in regenerative therapeutics offer potentially powerful medical tools to modify this pathology, with specific focus on (stem) cell transplantations. Multiple clinical trials have since reported overall beneficial outcomes favoring cell therapy. Nonetheless, the significance of these improvements is often not (clearly) discussed. As such, this narrative review aims to summarize the significance of the reported improvements from human clinical trials on IVD-targeted cell therapy. Methods: Through a comprehensive narrative review we discuss the improvements in pain, disability, quality of life, and imaging modalities and reported adverse events following cell therapy for discogenic pain. Results: Most clinical trials were able to report clear and significant improvements in pain and disability outcomes. Imaging and quality of life improvements however were not as clearly reported but did present some enhancements for a select number of patients. Finally, whether cell therapy can outperform placebo treatment remains intangible. Conclusions: Our review highlights the clinical significance of observed trends in pain and disability improvement. Nevertheless, reporting quality was found unsatisfactory and large-scale randomized controlled studies remain small in number. Future studies and articles should put more emphasis on improvements in imaging modalities and compare outcomes to (placebo) control groups to fully elucidate the efficacy and safety of cellular therapeutics against LBP.
Background: Recently, Tie2/TEK receptor tyrosine kinase (Tie2 or syn. angiopoietin-1 receptor) po... more Background: Recently, Tie2/TEK receptor tyrosine kinase (Tie2 or syn. angiopoietin-1 receptor) positive nucleus pulposus progenitor cells were detected in human, cattle, and mouse. These cells show remarkable multilineage differentiation capacity and direct correlation with intervertebral disc (IVD) degeneration and are therefore an interesting target for regenerative strategies. Nevertheless, there remains controversy over the presence and function of these Tie2 + nucleus pulposus cells (NPCs), in part due to the difficulty of identification and isolation. Purpose: Here, we present a comprehensive protocol for sorting of Tie2 + NPCs from human, canine, bovine, and murine IVD tissue. We describe enhanced conditions for expansion and an optimized fluorescence-activated cell sorting-based methodology to sort and analyze Tie2 + NPCs. Methods: We present flow cytometry protocols to isolate the Tie2 + cell population for the aforementioned species. Moreover, we describe crucial pitfalls to prevent loss of Tie2 + NPCs from the IVD cell population during the isolation process. A cross-species phylogenetic analysis of Tie2 across species is presented. Results: Our protocols are efficient towards labeling and isolation of Tie2 + NPCs. The total flow cytometry procedure requires approximately 9 hours, cell isolation 4 to 16 hours, cell expansion can take up to multiple weeks, dependent on the application, age, disease state, and species. Phylogenetic analysis of the TEK gene revealed a strong homology among species. Conclusions: Current identification of Tie2 + cells could be confirmed in bovine, canine, mouse, and human specimens. The presented flow cytometry protocol can successfully sort these multipotent cells. The biological function of isolated cells based on Tie2 + expression needs to be confirmed by functional assays such as in vitro differentiation. in vitro culture conditions to maintain and their possible proliferation of the Tie2 + fraction is the subject of future research.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundam... more The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundamental role in providing the spine with its unique structural and biomechanical functions. The inner part of the IVD contains the nucleus pulposus (NP), a gel-like tissue characterized by a high content of type II collagen and proteoglycans, which is crucial for the disc’s load-bearing and shock-absorbing properties. With aging and IVD degeneration (IDD), the NP gradually loses its physiological characteristics, leading to low back pain and additional sequelae. In contrast to surrounding spinal tissues, the NP presents a distinctive embryonic development since it directly derives from the notochord. This review aims to explore the embryology of the NP, emphasizing the pivotal roles of key transcription factors, which guide the differentiation and maintenance of the NP cellular components from the notochord and surrounding sclerotome. Through an understanding of NP development, we sought to investigate the implications of the critical developmental aspects in IVD-related pathologies, such as IDD and the rare malignant chordomas. Moreover, this review discusses the therapeutic strategies targeting these pathways, including the novel regenerative approaches leveraging insights from NP development and embryology to potentially guide future treatments.
Cell transplantation is being actively explored as a regenerative therapy for discogenic back pai... more Cell transplantation is being actively explored as a regenerative therapy for discogenic back pain. This study explored the regenerative potential of Tie2 + nucleus pulposus progenitor cells (NPPCs) from intervertebral disc (IVD) tissues derived from young (<25 years of age) and old (>60 years of age) patient donors. We employed an optimized culture method to maintain Tie2 expression in NP cells from both donor categories. Our study revealed similar Tie2 positivity rates regardless of donor types following cell culture. Nevertheless, clear differences were also found, such as the emergence of significantly higher (3.6-fold) GD2 positivity and reduced (2.7-fold) proliferation potential for older donors compared to young sources. Our results suggest that, despite obtaining a high fraction of Tie2 + NP cells, cells from older donors were already commi ed to a more mature phenotype. These disparities translated into functional differences, influencing colony formation, extracellular matrix production, and in vivo regenerative potential. This study underscores the importance of considering age-related factors in NPPC-based therapies for disc degeneration. Further investigation into the genetic and epigenetic alterations of Tie2 + NP cells from older donors is crucial for refining regenerative strategies. These findings shed light on Tie2 + NPPCs as a promising cell source for IVD regeneration while emphasizing the need for comprehensive understanding and scalability considerations in culture methods for broader clinical applicability.
Low back pain (LBP) and neck pain predominate as the primary causes of disability. Cell-and plate... more Low back pain (LBP) and neck pain predominate as the primary causes of disability. Cell-and platelet-rich plasma (PRP) products are potential therapies with clinical trials and reviews promoting their efficacy. Nonetheless, they frequently disregard the clinical significance of reported improvements. In this systematic review, the effectuated improvements in pain, disability, quality of life (QoL), and radiographic images are comprehensively described and scored on their clinical significance. An electronic database literature search was conducted on July 2023 for inhuman assessment of cell or PRP products to alleviate discogenic pain. Papers were screened on quantitative pain, disability, QoL, radiographic improvements, and safety outcomes. Risk of bias was assessed through MINORS and Cochrane Source of Bias tools. Reported outcomes were obtained, calculated, and assessed to meet minimal clinically important difference (MCID) standards. From 7623 screened papers, a total of 80 articles met the eligibility criteria, presenting 68 specific studies. These presented at least 1974 treated patients. Overall, cell/PRP injections could alleviate pain and disability, resulting in MCID for pain and disability in up to a 2-year follow-up, similar to those observed in patients undergoing spinal fusion. Included trials predominantly presented high levels of bias, involved heterogeneous study designs, and only a minimal number of randomized controlled trials. Nonetheless, a clear clinically significant impact was observed for cell-and PRP-treated cohorts with overall good safety
Purpose To investigate the therapeutic potential of extracellular vesicles (EVs) derived from hum... more Purpose To investigate the therapeutic potential of extracellular vesicles (EVs) derived from human nucleus pulposus cells (NPCs), with a specific emphasis on Tie2-enhanced NPCs, compared to EVs derived from human bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a coccygeal intervertebral disc degeneration (IDD) rat model. Methods EVs were isolated from healthy human NPCs cultured under standard (NPC STD-EVs) and Tie2-enhancing (NPC Tie2+-EVs) conditions. EVs were characterized, and their potential was assessed in vitro on degenerative NPCs in terms of cell proliferation and senescence, with or without 10 ng/mL interleukin (IL)-1β. Thereafter, 16 Sprague-Dawley rats underwent annular puncture of three contiguous coccygeal discs to develop IDD. Phosphate-buffered saline, NPC STD-EVs, NPC Tie2+-EVs, or BM-MSC-derived EVs were injected into injured discs, and animals were followed for 12 weeks until sacrifice. Behavioral tests, radiographic disc height index (DHI) measurements, evaluation of pain biomarkers, and histological analyses were performed to assess the outcomes of injected EVs. Results NPC-derived EVs exhibited the typical exosomal morphology and were efficiently internalized by degenerative NPCs, enhancing cell proliferation, and reducing senescence. In vivo, a single injection of NPC-derived EVs preserved DHI, attenuated degenerative changes, and notably reduced mechanical hypersensitivity. MSC-derived EVs showed marginal improvements over sham controls across all measured outcomes. Conclusion Our results underscore the regenerative potential of young NPC-derived EVs, particularly NPC Tie2+-EVs, surpassing MSC-derived counterparts. These findings raise questions about the validity of MSCs as both EV sources and cellular therapeutics against IDD. The study emphasizes the critical influence of cell type, source, and culture conditions in EV-based therapeutics.
Augmented reality (AR) is becoming more common and slowly being integrated into the surgical fiel... more Augmented reality (AR) is becoming more common and slowly being integrated into the surgical field. With the continuous progression of navigation and visualization techniques, AR has great potential to improve surgical quality and safety. Nevertheless, the effects of AR on surgical outcomes and surgeons' well-being remains poorly studied. The present prospective controlled study aims to assess the effect of surgery assisted with AR smart glasses on adolescent idiopathic scoliosis (AIS) deformity correction outcomes and surgeon fatigue.-METHODS: AIS patients scheduled for surgical deformity correction were prospectively recruited and assigned to standard or AR-supported surgery, using lightweight AR smart glasses. The demographic and clinical features were recorded. The pre-and postoperative spinal features, operative time, and blood loss were recorded and compared. Finally, the participating surgeons were asked to complete a questionnaire (e.g., visual analog scale for fatigue) to compare the effects of AR on their well-being.-RESULTS: Our results have shown enhanced spinal deformity corrections with Cobb angle (L35.7 vs. L46.9), thoracic kyphosis (8.1 vs. 11.6), and vertebral rotation (L9.3 vs. L13.8) changes favoring AR-supported surgery. Moreover, AR resulted in significantly lower violation rates per patient (7.5% vs. 6.6%; P [ 0.023). Finally, the visual analog scale for fatigue scores consistently showed a significant reduction in fatigue (5.7 AE 1.7 vs. 3.3 AE 1.2; P < 0.001) and other fatigue classifiers for the surgeons after AR-supported surgery.-CONCLUSIONS: Our controlled study has highlighted the enhanced spinal correction rates in AR-supported surgery and also improved surgeons' well-being and fatigue. These results endorse the adaptation of AR techniques to support AIS surgical correction.
Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebra... more Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebral disc (IVD) degeneration. Although oxidative stress has been shown to contribute to IVD degeneration, the underlying mechanisms remain undetermined. This study aimed to unravel the role of superoxide dismutase 2 (SOD2) in IVD pathogenesis and target oxidative stress to limit IVD degeneration. SOD2 demonstrated a dynamic regulation in surgically excised human IVD tissues, with initial upregulation in moderate degeneration and downregulation in severely degenerated IVDs. Through a comprehensive set of in vitro and in vivo experiments, we found a suggestive association between excessive mitochondrial superoxide, cellular senescence, and matrix degradation in human and mouse IVD cells. We confirmed that aging and mechanical stress, established triggers for IVD degeneration, escalated mitochondrial superoxide levels in mouse models. Critically, chondrocyte-specific Sod2 deficiency accelerated age-related and mechanical stress-induced disc degeneration in mice, and could be attenuated by β-nicotinamide mononucleotide treatment. These revelations underscore the central role of SOD2 in IVD redox balance and unveil potential therapeutic avenues, making SOD2 and mitochondrial superoxide promising targets for effective LBP interventions.
Low back pain (LBP) is a pervasive global issue causing substantial disability and significant ec... more Low back pain (LBP) is a pervasive global issue causing substantial disability and significant economic burden. The primary etiological factor behind LBP is intervertebral disc (IVD) degeneration, initiated in early adolescence and potentially leading to multiple spinal pathologies. However, current treatments for discogenic LBP are mainly palliative or involve invasive surgery, lacking disease-modifying therapies. Regenerative strategies, including cell therapy, may offer promising avenues to address the underlying pathology of IVD degeneration. Preclinical studies and clinical trials have demonstrated the potential of intradiscal cell transplantation to alleviate disc degeneration and associated pain with an overall favorable safety profile. Nonetheless, clinical trials present challenges, such as varying patient inclusion criteria, lack of adequate control groups, and short follow-up periods, necessitating cautious interpretation of results. This narrative review aims to provide an overview of clinical trials published to date and discuss the progress and translational hurdles of cell-based therapies for IVD degeneration and discogenic pain.
Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a... more Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a non-surgical alternative. This systematic review and meta-analysis aims to assess the efficacy and safety of chemonucleolytic enzymes for LDH. The primary objective is to evaluate efficacy through "treatment success" (i.e., pain reduction) and severe adverse events (SAEs) rates. Additionally, differences in efficacy and safety trends among chemonucleolytic enzymes are explored. Following our PROSPERO registered protocol (CRD42023451546) and PRISMA guidelines, a systematic search of PubMed and Web of Science databases was conducted up to July 18, 2023. Inclusion criteria involved human LDH treatment with enzymatic chemonucleolysis reagents, assessing pain alleviation, imaging changes, and reporting on SAEs, with focus on allergic reactions. Quality assessment employed the Cochrane Source of Bias and MINORS tools. Meta-analysis utilized odds ratios (OR) with 95% confidence intervals (CI). Among 62 included studies (12,368 patients), chemonucleolysis demonstrated an 79% treatment success rate and significantly outperformed placebo controls (OR 3.35, 95% CI 2.41-4.65) and scored similar to surgical interventions (OR 0.65, 95% CI 0.20-2.10). SAEs occurred in 1.4% of cases, with slightly higher rates in chymopapain cohorts. No significant differences in "proceeding to surgery" rates were observed between chemonucleolysis and control cohorts. Limitations include dated and heterogeneous studies, emphasizing the need for higher-quality trials. Further optimization through careful patient selection and advances in therapy implementation may further enhance outcomes. The observed benefits call for wider clinical exploration and adoption. No funding was received for this review.
Abstract: The intervertebral disc (IVD) is the largest avascular organ of the human body and play... more Abstract: The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundamental role in providing the spine with its unique structural and biomechanical functions. The inner part of the IVD contains the nucleus pulposus (NP), a gel-like tissue characterized by a high content of type II collagen and proteoglycans, which is crucial for the disc’s load-bearing and shock-absorbing properties. With aging and IVD degeneration (IDD), the NP gradually loses its physiological characteristics, leading to low back pain and additional sequelae. In contrast to surrounding spinal tissues, the NP presents a distinctive embryonic development since it directly derives from the notochord. This review aims to explore the embryology of the NP, emphasizing the pivotal roles of key transcription factors, which guide the differentiation and maintenance of the NP cellular components from the notochord and surrounding sclerotome. Through an understanding of NP development, we sought to investigate the implications of the critical developmental aspects in IVD-related pathologies, such as IDD and the rare malignant chordomas. Moreover, this review discusses the therapeutic strategies targeting these pathways, including the novel regenerative approaches leveraging insights from NP development and embryology to potentially guide future treatments.
Cell transplantation is being actively explored as a regenerative therapy for discogenic back pai... more Cell transplantation is being actively explored as a regenerative therapy for discogenic back pain. This study explored the regenerative potential of Tie2 + nucleus pulposus progenitor cells (NPPCs) from intervertebral disc (IVD) tissues derived from young (<25 years of age) and old (>60 years of age) patient donors. We employed an optimized culture method to maintain Tie2 expression in NP cells from both donor categories. Our study revealed similar Tie2 positivity rates regardless of donor types following cell culture. Nevertheless, clear differences were also found, such as the emergence of significantly higher (3.6-fold) GD2 positivity and reduced (2.7-fold) proliferation potential for older donors compared to young sources. Our results suggest that, despite obtaining a high fraction of Tie2 + NP cells, cells from older donors were already commi ed to a more mature phenotype. These disparities translated into functional differences, influencing colony formation, extracellular matrix production, and in vivo regenerative potential. This study underscores the importance of considering age-related factors in NPPC-based therapies for disc degeneration. Further investigation into the genetic and epigenetic alterations of Tie2 + NP cells from older donors is crucial for refining regenerative strategies. These findings shed light on Tie2 + NPPCs as a promising cell source for IVD regeneration while emphasizing the need for comprehensive understanding and scalability considerations in culture methods for broader clinical applicability.
The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a... more The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a rapid decline during aging and intervertebral disc degeneration, and has thus sparked interest in its utilization as a regenerative agent against disc degeneration. However, the challenge of maintaining and expanding these progenitor cells in vitro has been a significant hurdle. In this study, we investigated the potential of laminin-511 to sustain Tie2+ NP progenitor cells in vitro. We isolated cells from human NP tissue (n = 5) and cultured them for 6 days on either standard (Non-coat) or iMatrix-511 (laminin-511 product)-coated (Lami-coat) dishes. We assessed these cells for their proliferative capacity, activation of Erk1/2 and Akt pathways, as well as the expression of cell surface markers such as Tie2, GD2, and CD24. To gauge their regenerative potential, we examined their extracellular matrix (ECM) production capacity (intracellular type II collagen (Col2) and proteoglycans (PG))...
The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a... more The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a rapid decline during aging and intervertebral disc degeneration, and has thus sparked interest in its utilization as a regenerative agent against disc degeneration. However, the chal- lenge of maintaining and expanding these progenitor cells in vitro has been a significant hurdle. In this study, we investigated the potential of laminin-511 to sustain Tie2+ NP progenitor cells in vitro. We isolated cells from human NP tissue (n = 5) and cultured them for 6 days on either standard (Non-coat) or iMatrix-511 (laminin-511 product)-coated (Lami-coat) dishes. We assessed these cells for their proliferative capacity, activation of Erk1/2 and Akt pathways, as well as the expression of cell surface markers such as Tie2, GD2, and CD24. To gauge their regenerative po- tential, we examined their extracellular matrix (ECM) production capacity (intracellular type II collagen (Col2) and proteoglycans (PG)) and their ability to form spherical colonies within methyl- cellulose hydrogels. Lami-coat significantly enhanced cell proliferation rates and increased Tie2 expression, resulting in a 7.9-fold increase in Tie2-expressing cell yields. Moreover, the overall pro- portion of cells positive for Tie2 also increased 2.7-fold. Notably, the Col2 positivity rate was signifi- cantly higher on laminin-coated plates (Non-coat: 10.24% (±1.7%) versus Lami-coat: 26.2% (±7.5%), p = 0.010), and the ability to form spherical colonies also showed a significant improvement (Non-coat: 40.7 (±8.8)/1000 cells versus Lami-coat: 70.53 (±18.0)/1000 cells, p = 0.016). These findings demon- strate that Lami-coat enhances the potential of NP cells, as indicated by improved colony formation and proliferative characteristics. This highlights the potential of laminin-coating in maintaining the NP progenitor cell phenotype in culture, thereby supporting their translation into prospective clinical cell-transplantation products.
Background: Rubinstein-Taybi syndrome (RTS) is a rare disorder with a range of congenital anomali... more Background: Rubinstein-Taybi syndrome (RTS) is a rare disorder with a range of congenital anomalies. Although 40% to 60% of patients with RTS have scoliotic deformities, few reports discuss the outcomes of correctional surgery and postoperative care. To raise awareness of the clinical features of RTS and surgical considerations, the authors report on the surgical treatment of a pediatric patient with RTS accompanied by scoliosis. Observations: A 14-year-old girl with RTS presented with low back pain associated with progressive scoliosis. Because of jaw hypoplasia, videolaryngoscopy-mediated intubation was chosen. A single-stage T4-L3 posterior corrective fusion with instrumentation was successfully performed. Physical and imaging findings were analyzed up to 2 years after correction. The main thoracic Cobb angle was corrected from 73° to 12° and maintained for 2 years after surgery. The patient's low back pain resolved. Lessons: Careful consideration of RTS-associated complications and preoperative planning, including the use of videolaryngoscopy-mediated intubation, anesthesia selection, and postoperative care, proved crucial. Scoliosis may appear in many variations in rare diseases such as RTS. Publication of case reports such as this one is needed to provide detailed information about strategies and considerations for correcting scoliotic deformities in patients with RTS.
International Journal of Molecular Sciences, Apr 29, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
North American Spine Society Journal (nassj), Mar 1, 2023
Background: Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain ... more Background: Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain (LBP) and despite a prominent prevalence, present treatment options remain inadequate for a large portion of LBP patients. New developments in regenerative therapeutics offer potentially powerful medical tools to modify this pathology, with specific focus on (stem) cell transplantations. Multiple clinical trials have since reported overall beneficial outcomes favoring cell therapy. Nonetheless, the significance of these improvements is often not (clearly) discussed. As such, this narrative review aims to summarize the significance of the reported improvements from human clinical trials on IVD-targeted cell therapy. Methods: Through a comprehensive narrative review we discuss the improvements in pain, disability, quality of life, and imaging modalities and reported adverse events following cell therapy for discogenic pain. Results: Most clinical trials were able to report clear and significant improvements in pain and disability outcomes. Imaging and quality of life improvements however were not as clearly reported but did present some enhancements for a select number of patients. Finally, whether cell therapy can outperform placebo treatment remains intangible. Conclusions: Our review highlights the clinical significance of observed trends in pain and disability improvement. Nevertheless, reporting quality was found unsatisfactory and large-scale randomized controlled studies remain small in number. Future studies and articles should put more emphasis on improvements in imaging modalities and compare outcomes to (placebo) control groups to fully elucidate the efficacy and safety of cellular therapeutics against LBP.
Background: Recently, Tie2/TEK receptor tyrosine kinase (Tie2 or syn. angiopoietin-1 receptor) po... more Background: Recently, Tie2/TEK receptor tyrosine kinase (Tie2 or syn. angiopoietin-1 receptor) positive nucleus pulposus progenitor cells were detected in human, cattle, and mouse. These cells show remarkable multilineage differentiation capacity and direct correlation with intervertebral disc (IVD) degeneration and are therefore an interesting target for regenerative strategies. Nevertheless, there remains controversy over the presence and function of these Tie2 + nucleus pulposus cells (NPCs), in part due to the difficulty of identification and isolation. Purpose: Here, we present a comprehensive protocol for sorting of Tie2 + NPCs from human, canine, bovine, and murine IVD tissue. We describe enhanced conditions for expansion and an optimized fluorescence-activated cell sorting-based methodology to sort and analyze Tie2 + NPCs. Methods: We present flow cytometry protocols to isolate the Tie2 + cell population for the aforementioned species. Moreover, we describe crucial pitfalls to prevent loss of Tie2 + NPCs from the IVD cell population during the isolation process. A cross-species phylogenetic analysis of Tie2 across species is presented. Results: Our protocols are efficient towards labeling and isolation of Tie2 + NPCs. The total flow cytometry procedure requires approximately 9 hours, cell isolation 4 to 16 hours, cell expansion can take up to multiple weeks, dependent on the application, age, disease state, and species. Phylogenetic analysis of the TEK gene revealed a strong homology among species. Conclusions: Current identification of Tie2 + cells could be confirmed in bovine, canine, mouse, and human specimens. The presented flow cytometry protocol can successfully sort these multipotent cells. The biological function of isolated cells based on Tie2 + expression needs to be confirmed by functional assays such as in vitro differentiation. in vitro culture conditions to maintain and their possible proliferation of the Tie2 + fraction is the subject of future research.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
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