
==== Front
Front Bioeng Biotechnol
Front Bioeng Biotechnol
Front. Bioeng. Biotechnol.
Frontiers in Bioengineering and Biotechnology
2296-4185
Frontiers Media S.A.

1417600
10.3389/fbioe.2024.1417600
Bioengineering and Biotechnology
Review
Regenerative therapies for lumbar degenerative disc diseases: a literature review
Sono et al.
10.3389/fbioe.2024.1417600
Sono Takashi *

Shima Koichiro
Shimizu Takayoshi
Murata Koichi

Matsuda Shuichi

Otsuki Bungo
Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Edited by: Pablo Taboada, University of Santiago de Compostela, Spain

Reviewed by: Peikai Chen, The University of Hong Kong, China

Caihong Zhu, Soochow University Medical College, China

*Correspondence: Takashi Sono, ts466241@kuhp.kyoto-u.ac.jp
26 8 2024
2024
12 141760012 5 2024
19 8 2024
Copyright © 2024 Sono, Shima, Shimizu, Murata, Matsuda and Otsuki.
2024
Sono, Shima, Shimizu, Murata, Matsuda and Otsuki
https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
This review aimed to summarize the recent advances and challenges in the field of regenerative therapies for lumbar disc degeneration. The current first-line treatment options for symptomatic lumbar disc degeneration cannot modify the disease process or restore the normal structure, composition, and biomechanical function of the degenerated discs. Cell-based therapies tailored to facilitate intervertebral disc (IVD) regeneration have been developed to restore the IVD extracellular matrix or mitigate inflammatory conditions. Human clinical trials on Mesenchymal Stem Cells (MSCs) have reported promising outcomes exhibited by MSCs in reducing pain and improving function. Nucleus pulposus (NP) cells possess unique regenerative capacities. Biomaterials aimed at NP replacement in IVD regeneration, comprising synthetic and biological materials, aim to restore disc height and segmental stability without compromising the annulus fibrosus. Similarly, composite IVD replacements that combine various biomaterial strategies to mimic the native disc structure, including organized annulus fibrosus and NP components, have shown promise. Furthermore, preclinical studies on regenerative medicine therapies that utilize cells, biomaterials, growth factors, platelet-rich plasma (PRP), and biological agents have demonstrated their promise in repairing degenerated lumbar discs. However, these therapies are associated with significant limitations and challenges that hinder their clinical translation. Thus, further studies must be conducted to address these challenges.

lumbar degenerative disc disease
regenerative therapy
cell therapy
biomaterials
growth factors
animal models
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by JSPS KAKENHI Grant number JP24K19575.section-at-acceptanceTissue Engineering and Regenerative Medicine
==== Body
pmc1 Introduction

Lumbar degenerative disc disease (LDDD), an age-associated disease characterized by severe back pain and disability (Ohtori et al., 2015), is highly prevalent across the world. The pathogenesis of LDDD involves age-related (Ohnishi et al., 2018) or injury-induced (Wang et al., 2023) degeneration of the intervertebral discs (IVDs). Decreased hydration, reduced proteoglycan content, loss of disc height, annular fissuring, and ingrowth of nerve and blood vessels (Fujii et al., 2019) are observed in degenerating discs. These changes can lead to structural breakdown, biomechanical dysfunction, instability, herniation, and nerve compression. Current treatment options, such as medications (Chaparro et al., 2014), physical therapy (Hayden et al., 2021), cognitive functional therapy (Kent et al., 2023), epidural injections (Deyo and Mirza, 2016), and spinal fusion procedures (Otsuki et al., 2023; Shimizu et al., 2021), only provide temporary symptomatic relief. A treatment strategy that can restore normal disc structure, composition, and function remains to be established. Tissue engineering aims to repair and regenerate discs using cells, biomaterials, growth factors, and platelet-rich plasma (PRP). This literature review summarized the recent advances and challenges in the field of regenerative therapies for lumbar disc degeneration.

2 Disc structure and degeneration

IVDs comprise a central gelatinous nucleus pulposus surrounded by the annulus fibrosus and cartilaginous endplates. The proteoglycan-rich nucleus is capable of absorbing water and resisting compressive load. The collagen fibers constituting the highly organized lamellar annulus fibrosus provide tensile strength (Sakai and Andersson, 2015). The proteoglycan and water content of the discs reduces with aging and injury. In addition, further changes, such as disorganized matrix; loss of collagen organization; ingrowth of nerves and vessels; decreased cell viability; and increased inflammatory cytokine (IL-1β, IL-6, and TNF-α), C-reactive protein levels, and type II collagen levels, have also been reported (Khan et al., 2017; de Queiroz et al., 2016; Stürmer et al., 2005; Wang et al., 2010; Goode et al., 2012) (Figure 1). These molecular changes result in structural breakdown, reduction in disc height, annular fissuring, radial bulging, altered biomechanics, nerve compression, instability, herniation, and lower back pain.

FIGURE 1 The scheme summarizing the modalities of the regenerative therapies and the pathological conditions of the intervertebral disc degeneration.

3 Current treatments

The first-line treatment options for symptomatic LDDD include the administration of medications, such as non-steroidal anti-inflammatory drugs, muscle relaxants, and opioids, to alleviate pain (Chaparro et al., 2014; Deyo and Mirza, 2016). Physical therapy aims to strengthen core muscles, thereby improving ergonomics (Hayden et al., 2021). Short-term pain relief can be achieved with epidural steroid injections and intradiscal electrothermal therapy (Deyo and Mirza, 2016). Spinal fusion procedures using cages and screws have been performed to stabilize the affected segments in severe cases; however, this can result in increased stress on adjacent segments (Otsuki et al., 2023; Shimizu et al., 2021). Discectomy is performed to remove herniated nucleus material compressing the nerves (Özer and Demirtaş, 2023; Goparaju et al., 2023). Disc arthroplasty involves the replacement of degenerated discs with artificial implants (van den Eerenbeemt et al., 2010; Siepe et al., 2014; Gornet et al., 2017; Park et al., 2018). Nevertheless, the inability of these approaches to modify the disease process or restore the normal structure, composition, and biomechanical function of the degenerated discs underscores the requirement for developing biological therapies that facilitate disc regeneration.

4 Cell sources

Cell therapy is an innovative treatment approach that involves infusing living cells into a patient to repair or replace damaged tissue or modify the behavior of local cells (Sakai and Andersson, 2015). Cell-based therapies tailored to facilitate IVD regeneration in patients with IVD degeneration have been developed to restore the IVD extracellular matrix (ECM) or mitigate the inflammatory conditions that are characteristic of disc deterioration (Fujii et al., 2019; Sakai et al., 2022). Measures should be taken to ensure that the transplanted cells thrive within the hostile environment of a degenerating IVD by directly contributing to ECM synthesis and inducing a reparative shift in native cell activity via paracrine signaling or by facilitating the arrival of regenerative cells and preventing the infiltration of harmful cells. This would help achieve successful treatment outcomes. Animal studies have demonstrated the potential of cell transplantation to decelerate or halt degenerative processes in some cases (Hiraishi et al., 2018; Nukaga et al., 2019). Minimally invasive procedures, such as a needle injection under image guidance, are used to introduce the cells into the IVD. The cells can be encapsulated in supportive matrices to enhance retention and functionality.

Mesenchymal stem cells (MSCs) have attracted considerable interest in recent years. MSCs derived from the bone marrow (Orozco et al., 2011; Elabd et al., 2016; Henriksson et al., 2019; Noriega et al., 2017; Amirdelfan et al., 2021), adipose tissue (Kumar et al., 2017), peripheral blood (Haufe and Mork, 2006), or umbilical cords (Pang et al., 2014; Lewandrowski et al., 2023) exhibit potential for chondrogenic differentiation and high proliferative ability. Furthermore, they can be harvested easily from autologous and allogeneic sources. MSCs exhibit remarkable versatility, including the capacity for immunomodulation. This property could be beneficial in tempering the inflammatory environment of the IVD (Weiss and Dahlke, 2019). Environmental stressors within the IVD can affect the proliferation and differentiation capabilities of MSCs; thus, the adaptability and survival of MSCs within IVDs require further study (Gay et al., 2019).

Human clinical trials have predominantly focused on MSCs owing to the promising outcomes exhibited by MSCs in reducing pain and improving function in patients with IVD degeneration (Table 1). Trials using adipose- and bone marrow-derived MSCs have reported improvement in pain and disability scores (Orozco et al., 2011; Elabd et al., 2016; Henriksson et al., 2019; Noriega et al., 2017; Amirdelfan et al., 2021; Kumar et al., 2017; Pang et al., 2014; Lewandrowski et al., 2023). Moreover, the safety profiles of MSCs are generally favorable, and the incidence of serious adverse events is rare (Amirdelfan et al., 2021), underscoring the potential viability of MSC therapies.

TABLE 1 Cell therapies for degenerative disc disease.

Author	Year	Trial	Cells	Cell number	Number of patients	Outcomes	Follow-up period (months)	Adverse events	
Orozco (Orozco et al., 2011)	2011	Phase 1/2	Autologous BM-MSCs	1.0 × 107	10	Significant improvement in VAS, OD,SF-36	12	None	
Elabd (Elabd et al., 2016)	2016	case series	Autologous BM-MSCs	1.5 × 107–5.2 × 107	5	Improvement in strength and mobility	48–60	None	
Henriksson (Henriksson et al., 2019)	2019	case series	Autologous BM-MSCs	1.0 × 106	4	Not mentioned	8–28	One deterioration in low back pain	
Noriega (Noriega et al., 2017)	2017	RCT, Phase 1/2	Allogenic BM-MSCs	2.5 × 107	12	Significant improvement in VAS and OD	12	None	
Amirdelfan (Amirdelfan et al., 2021)	2021	RCT, Phase 2	Allogenic BM-MSCs	6.0 × 106–1.8 × 107	60	Improvement in VAS and ODI	36	One implantation site infection	
Kumar (Kumar et al., 2017)	2017	Phase I	Autologous AD-MSCs	2.0 × 107–4.0 × 107	10	Significant improvement in VAS, ODI, SF-36	12	None	
Haufe (Haufe and Mork, 2006)	2006	case series	Autologous HSCs	NA	10	No improvement in pain	12	None	
Pang (Pang et al., 2014)	2014	case series	Allogenic UC-MSCs	1.0 × 107	2	Improvement in VAS and ODI	24	None	
Lewandrowski (Lewandrowski et al., 2023)	2023	case series	Allogenic UC-MSCs	5.0 × 106	33	Significant improvement in VAS and ODI	24	None	
Mochida (Mochida et al., 2015)	2015	case series	Autologous NP cells	1.0 × 106	9	Improvement in JOA score and lumbar back pain	36	None	
Beall (Beall et al., 2021)	2021	RCT	Allogenic spine-derived cells	>6.0 × 106	123	Significant improvement in ODI and VAS	12	2/141 SAEs	
Coric (Coric et al., 2013)	2013	Phase 1	Allogenic chondrocytes	1.0 × 107–2.0 × 107	15	Significant improvement in NRS, ODI, and SF-36	12	None	
Tschugg (Tschugg et al., 2017)	2017	RCT, Phase 1/2	Autologous disc-derived chondrocytes	3.6 × 106–4.4 × 106	12	Not mentioned	1.5	6/12 TEAEs	
Comella (Comella et al., 2017)	2017	case series	Autologous SVF cells/PRP	3.0 × 107–6.0 × 107	15	Significant improvement in VAS, PPI, and SF-12	12	None	
Pettine (Pettine et al., 2015)	2015	case series	Autologous BMC	1.2 × 107	26	Significant improvement in ODI, VAS	12	None	
Tuakli-Wosornu (Tuakli-Wosornu et al., 2016)	2016	RCT	PRP	NA	29	Significant improvement in NRS and function	12	None	
Akeda (Akeda et al., 2022)	2022	RCT	PRP	NA	9	Significant improvement in RDQ and JOABPEQ	60	One post-injection pain	
BM, bone marrow-derived; MSC, mesenchymal stem cell; VAS, visual analog scale; ODI, oswestry disability index; SF, Short Form. RCT, randomized controlled trial; AD, adipose-derived; HSC, hematopoietic precursor stem cell; UC, umbilical cord-derived; NP, nucleus pulposus. JOA, japanese orthopedic association; SAEs, serious adverse events; TEAEs, treatment-related adverse events; SVF, stromal vascular fraction. PRP, platelet-rich plasma; PPI, present pain index; BMC, bone marrow concentrate; NRS, numeric rating scale; RDQ, roland morris disability questionnaire. BPEQ, back pain evaluation questionnaire.

Studies on other types of cells, such as the nucleus pulposus (NP) cells (Mochida et al., 2015; Beall et al., 2021) and chondrocytes from articular or hyaline cartilage (Coric et al., 2013; Tschugg et al., 2017), have elucidated the unique regenerative capacities inherent to cells native to avascular tissues, such as the IVD. However, the limitations associated with accessibility and phenotypic stability limit the widespread application of these treatment strategies. Clinical application of these cells, although limited, suggests their safety and potential efficacy in improving the status of the IVD and patient outcomes.

The treatment outcomes of emerging therapies utilizing less-defined cell products, such as stromal vascular fraction (SVF) (Comella et al., 2017) and bone marrow concentrate (BMC) (Pettine et al., 2015), vary. These complex mixtures, which comprise various types of cells and bioactive factors, offer a multifaceted approach to tissue regeneration. The precise mechanisms of action and individual contributions of these components are unclear; however, early results suggest a potential for facilitating significant clinical improvement in certain cases (Comella et al., 2017; Pettine et al., 2015). Nevertheless, the heterogeneity of these products hinders standardization and quality control.

Animal experiments have used iPS cells as a cell source and induced differentiation into notochordal cells (Sheyn et al., 2019), nucleus pulposus-like cells (Zhang et al., 2020), or cartilaginous tissue (Kamatani et al., 2022). These cells were transplanted into IVDs subsequently. Their application in human beings is anticipated in the future.

5 Biomaterials and scaffolds

Biomaterials aimed at NP replacement in IVD regeneration, comprising synthetic and biological materials designed to restore disc height and segmental stability without compromising the annulus fibrosus, are predominantly injectable materials (Iatridis et al., 2013; Mehrkens et al., 2012). The properties of synthetic materials must match the mechanical properties of the native disc to achieve successful outcomes. This ensures the integration of the material with the surrounding structures and the restoration of the motion characteristics without inducing adverse immune responses. Furthermore, durability and minimal wear-debris generation are critical factors affecting clinical viability (Bowles and Setton, 2017; Li et al., 2022).

Biologically based materials can be remodeled by the body. Consequently, a different set of criteria, primarily focusing on the ability to support cell-mediated tissue regeneration, must be satisfied by these materials to achieve successful outcomes. This category comprises materials that serve as cell-delivery vehicles to promote NP tissue regeneration (Bowles and Setton, 2017; Li et al., 2022).

Initial strategies for NP replacement involved the administration of synthetic polymers that hydrate in situ to mimic the natural hydration of NP. This approach aimed to restore disc pressure and height. Copolymeric hydrogel (polyacrylonitrile [PAN] and polyacrylamide) encased in a polyethylene jacket (PDNTM) is one such combination (Ray, 2002). Other materials, such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) reinforced with a Dacron mesh (NeuDisc™) (Bertagnoli et al., 2005),hydrating PAN (NucleoFix™/Gelstix™) (Bowles and Setton, 2017; Ceylan et al., 2019; Koetsier et al., 2022), in situ curing polymer using inflatable polyurethane balloon (DASCOR™) (Tsantrizos et al., 2008; Ahrens et al., 2009), in situ curing polymerized water-in-oil emulsion composite (DiscCell™) (Pelletier et al., 2016), glutaraldehyde cross-linked elastin and silk polypeptide (BioDisc™) (Yuksel et al., 2002), and hydrogel of a chemically cross-linked elastin and silk polypeptide (NuCore™) (Berlemann and Schwarzenbach, 2009) have also been used. However, these materials are associated with significant limitations such as uncontrolled swelling, mechanical complications (e.g., stiffness), and device migration. Clinical trials have explored various materials, such as hydrogels and polymers (Ceylan et al., 2019; Koetsier et al., 2022; Ahrens et al., 2009; Berlemann and Schwarzenbach, 2009), that can transition into a gel or solid state in situ, to minimize the damage to the annulus fibrosus during implantation. Ceylan et al. (2019) reported GelStixTM demonstrated mean VAS score and ODI score improvement after implantation. Moreover, RCT is being conducted (NCT 02763956) (Koetsier et al., 2022). However, progress in the domain of market approval has been limited (Bowles and Setton, 2017) (Table 2) owing to the focus on mechanical restoration rather than biological integration or interaction with local cells.

TABLE 2 Clinical and preclinical results of the nucleus pulposus repair or replacement devices.

Trade name	Classification	Polymer	Outcomes	
NeuDisc™ (Bertagnoli et al., 2005)	injectable	Copolymer of polyvinyl alcohol and polyvinyl pyrrolidine or modified PAN reinforced by a Dacron mesh	Force to failure 3581N in compression	
NucleoFix™
/GelStix™ (Bowles and Setton, 2017) (Ceylan et al., 2019) (Koetsier et al., 2022)	injectable	Hydrating PAN	Mean VAS score and ODI score were improved significantly
RCT is being conducted (NCT02763956)	
DASCOR™ (Tsantrizos et al., 2008) (Ahrens et al., 2009)	in situ forming	in situ curing polymer using inflatable polyurethane balloon	4.2–5.6 MPa compressive strength
Significant improvements in mean ODI and VAS scores	
DiscCell™ (Pelletier et al., 2016)	in situ forming	in situ curing polymerized water-in-oil emulsion composite	Restoring segmental range of motion in vitro	
BioDisc™ (Yuksel et al., 2002)	in situ forming	Glutaraldehyde cross-linked elastin and silk polypeptide	Mechanical durability of the implant was demonstrated through 10 million compressive loading cycles	
NuCore™ (Berlemann and Schwarzenbach, 2009)	in situ forming	Hydrogel of a chemically cross-linked elastin and silk polypeptide	Significant improvement for leg and back pain, as well as function scores	
PAN, polyacrylonitrile; VAS, visual analog scale; ODI, oswestry disability index; RCT, randomized controlled trial.

Engineering complete IVD replacements using materials that facilitate cellular survival and matrix remodeling has garnered interest in recent years, indicating a trend toward the use of more biologically integrated solutions. Composite IVD replacements that combine various biomaterial strategies to mimic the native disc structure, including organized annulus fibrosus and NP components, have shown promise (Mizuno et al., 2006; Sakai et al., 2006; Nesti et al., 2008; Nerurkar et al., 2010; Zhuang et al., 2011; Bowles et al., 2011; Park et al., 2012; Martin et al., 2014; Choy and Chan, 2015; Chik et al., 2015; Ukeba et al., 2021) (Table 3). This strategy aims to replicate the appearance and mechanical functions of the native disc; however, it has exhibited varying degrees of success in mimicking the mechanical properties and achieving integration with the native tissue.

TABLE 3 Overview of the composite materials with cells.

Author	Year	Materials	Donor cells	Recipients	Outcomes	
Mizuno (Mizuno et al., 2006)	2006	PGA/alginate gel	sheep AF cells/NP cells	mice	Proteoglycan, collagen content and compressive mechanical properties were similar to native NP cells	
Sakai (Sakai et al., 2006)	2006	atelocollagen	rabbit bone marrow derived MSCs	rabbit	Regained disc height, proteoglycan accumulation and T2-weighted signal intensity in MRI	
Nesti (Nesti et al., 2008)	2008	PLLA/HA	human bone marrow derived MSCs	NA	The composite IVD expressed type 1,2,9,10,11 collagen and aggrecan	
Nerurkar (Nerurkar et al., 2020)	2010	electrospun PCL/agarose	bovine AF cells/bone derived MSCs	NA	Appropriate ECM deposition was found in the composite IVD	
Zhuang (Zhuang et al., 2011)	2011	DBM/collagen2/hyaluronate/chondroitin-6-sulfate	rabbit AF cells/NP cells	mice	Collagen and proteoglycan deposition was found in the composite IVD	
Bowles (Bowles et al., 2011)	2011	contracted collagen gel/alginate	ovine AF cells/NP cells	rat	Disc height was maintained in half of the implants	
Park (Perk et al., 2012)	2012	porous silk/fibrin/HA hydrogel	porchine AF cells/chondrocytes	NA	Implanted AF cells and chondrocytes demonstrated appropriate gene expression and GAG especially in the lamellar silk scaffold	
Martin (Martin et al., 2014)	2014	electrospun PCL	None	rat	Construct was stable in 47% of samples without external fixation and cell infiltration into implants was found	
Choy (Choy and Chan, 2015)	2015	photochemically crosslinked collagen membranes/collagen-GAGs
co-precipitate	None	NA	Composite IVD showed as good performance as the native disc on mechanical testing	
Chik (Chika et al., 2015)	2015	contracted collagen gel, collagen-GAGs co-precipitate	rabbit bone marrow derived MSCs	NA	Engineered IVD showed appropriate histological features	
Ukeba (Ukeba et al., 2021)	2021	ultra-purified alginate gel	bone marrow derived stem cell/bone marrow aspirate concentrate	rabbit	Composite IVD demonstrated good mechanical properties and enhanced repair of IVD defects in rabbits	
PGA, polyglycolic acid; AF, annulus fibrosus; NP, nucleus pulposus; MRI, magnetic resonance image; ECM, extracellular matrix; IVD, intervertebral disc; PLLA, poly L-lactic acid; HA, hyaluronic acid; NA, not assessed; DBM, demineralized bone matrix. MSC, mesenchymal stem cell; GAG, glycosaminoglycan; PCL, poly ε-caprolactone.

Challenges related to the management of the disc space, integration with the native tissue, and the mechanical environment of the spine have been reported by in vivo animal studies on composite discs. These findings emphasize the requirement for conducting further research to address these limitations that hinder successful clinical translation (Mizuno et al., 2006; Sakai et al., 2006; Zhuang et al., 2011; Bowles et al., 2011; Martin et al., 2014; Ukeba et al., 2021). Techniques to engineer motion segments, including the disc and adjacent bony structures, aim to overcome the challenges associated with integration and improve patient outcomes.

Although promising, the field of IVD regeneration through NP replacement is associated with several limitations associated with material design, biological integration, and mechanical performance. Thus, further studies must be conducted in the future to better understand and overcome these obstacles for successful clinical application.

6 Growth factors, PRP, and biologics

Growth factors, such as TGF-β (Sun et al., 2023; Risbud et al., 2006); GDF-5,6 (Gantenbein-Ritter et al., 2011; Clarke et al., 2014); FGF-2 (Tsai et al., 2007); IGF-1 (Osada et al., 1996); BMP-2, 4, and 7 (Tim et al., 2003; Du et al., 2022; Ellman et al., 2013); and CTGF (Matta et al., 2018), have been evaluated in previous studies (Table 4) These factors can stimulate matrix synthesis, cell proliferation, and differentiation. However, concerns regarding spatiotemporal delivery and uncontrolled differentiation remain.

TABLE 4 Growth factors associated with intervertebral disc regeneration.

Author	Year	Name of growth factor	Dose	Animals	Outcomes	
Sun (Sun et al., 2023)	2023	TGF-β1	Plasmid	Human NP cells	Modulating oxidative stress	
Risbud (Risbud et al., 2006)	2006	TGF-β3	10 ng/mL	Rat NP and AF cells	Maintenance of phenotype	
Gantenbein Ritter (Gantenbein-Ritter et al., 2011)	2011	GDF-5	100 ng/mL	Human BMSCs	Upregulation of Col2, ACAN	
Clarke (Clarke et al., 2014)	2014	GDF-6	100 ng/mL	AD-MSCs, BM-MSCs	Upregulation of Col2, ACAN and NP marker	
Tsai (Tsai et al., 2007)	2007	FGF-2	10 ng/mL	Bovine NP cells	Maintenance of phenotype	
Osada (Osada et al., 1996)	1996	IGF-1	100 ng/mL	Bovine NP cells	Proteoglycan synthesis	
Yoon (Tim et al., 2003)	2003	BMP-2	1000 ng/mL	Rat AF cells	Upregulation of Col2, ACAN and Sox9	
Du (Du et al., 2022)	2022	BMP-4	68 ng/mL	Sheep NP and AF cells	Upregulation of Sox9 and increased ECM production	
Ellman (Ellman et al., 2013)	2013	BMP-7	100 ng/mL	Bovine NP cells	PG synthesis and upregulation of ACAN	
Matta (Matta et al., 2018)	2018	CTGF	100 ng/mL	Human NP cells, rat, dog	Suppression of inflammation and upregulation of Col2, ACAN	
TGF, transforming growth factor; NP, nucleus pulposus; AF, annulus fibrosus; GDF, growth differentiation factor. BMSC, bone marrow-derived stem cell; Col2, type II collagen; ACAN, aggrecan; AD, adipose-derived. MSC, mesenchymal stem cell; BM, bone marrow-derived; FGF, fibroblast growth factor; IGF, insulin-like growth factor. BMP, bone morphogenetic protein; Sox9, SRY-Box Transcription Factor 9; ECM, extracellular matrix; PG, proteoglycan. CTGF, connective tissue growth factor.

Injecting GDF-6 into the IVD attenuated inflammatory gene expression and improved disc degeneration in a rabbit puncture model (Miyazaki et al., 2018). Phase 1/2 clinical trials on the intradiscal injection of recombinant human growth and differentiation factor-5 (rhGDF-5) have reported promising results (NCT00813813 and NCT01124006).

PRP, which comprises concentrated autologous platelets and growth factors (Akeda et al., 2019), has shown potential in increasing cell proliferation, matrix production, and disc height in preclinical models. PRP can be classified into four categories, comprising four types of preparation, based on the number of leukocytes and fibrin content (Akeda et al., 2019). Two randomized controlled trials have investigated the effects of PRP. Tuakli-Wosornu et al. reported that injecting PRP into the IVD resulted in significant improvement in lower back pain and function over 8 weeks; moreover, the improvement was maintained at the 1-year follow-up visit (Tuakli-Wosornu et al., 2016). Akeda et al. reported that injecting PRP into the IVD resulted in a significant improvement in the disability score at 26 weeks and walking ability scores at 4 and 8 weeks compared with those achieved with corticosteroid injection (Akeda et al., 2022) (Table 1). Optimal formulations and delivery methods continue to be explored. Small molecules and drugs aim to inhibit inflammatory cytokines and MMPs, while also regulating the expression of catabolic/anabolic genes.

Nuclear factor-κB (NF-κB) decoy and TNF-α inhibitors are biologics that exert anti-inflammatory effects. NF-κB, a transcription factor, regulates the inflammatory cytokine levels. NF-κB decoy, an oligodeoxynucleotide containing the NF-κB binding site that entraps NF-κB subunits, can suppress NF-κB activity. Intradiscal injection of NF-κB can suppress inflammatory gene expression in degenerated discs and restore disc height loss (Kato et al., 2021). Notably, intradiscal injection of a TNF-α inhibitor (etanercept) improved discogenic pain in humans within a 2-month follow-up period in a previous study (Sainoh et al., 2016).

7 Multi-strategy synergistic therapy

In recent years, studies on the multi-strategy synergistic therapies that incorporate cells, biomaterials, and growth factors for intervertebral disc degeneration have also been conducted. Wei et al. reported that TGF-1 was embedded with MSCs in decellularized annulus fibrosus matrix (DAFM) hydrogels reinforced with polyethylene glycol diacrylate (PEGDA) to facilitate the controlled release of TGF-1 while preserving the hydrogel’s porous structure. Following infusion into a rat model with AF injury, there was a notable increase in the migration of AF cells to the injury site, which promoted anabolic upregulation (Wei et al., 2022). Sun et al. (2020) utilized 3D printing and electrospinning technology to load TGF-β3, CTGF and bone marrow-derived MSCs onto polydopamine nanoparticles and polycaprolactone scaffolds, respectively, mimicking the structure of AF and achieving mechanical properties similar to those of natural AF in the rodents. Although these studies have demonstrated that multi-strategy combination has great potential for IVD repair, further studies in large animal models are necessary.

8 Animal models

In vitro and in vivo studies have been conducted using small and large animal models of rodents (such as mice and rats), rabbits; dogs; sheep; goats; pigs; and monkeys; to evaluate regenerative techniques (Poletto et al., 2023). The use of small animal models is a cost-effective approach for screening. Rodents, such as mice and rats, are the most commonly used animal species (54%) in IVD studies (Poletto et al., 2023). However, the physiological characteristics of rodents vary from those of humans. In contrast, the disc size and disc degeneration observed in large animals, such as dogs, sheep, and pigs, is similar to that in humans; nevertheless, replicating the slow, progressive human disc pathology in these animals is difficult. IVD degeneration can be induced via bacterial, chemical, genetic, noninvasive, spontaneous, and surgical methods (Poletto et al., 2023; Oichi et al., 2020). The experimental time points vary depending on the species. The commonly used time points for different species are as follows: rodents, 2 or 4 weeks; rabbits, 4 weeks; sheep, 24 weeks; goats, 12 weeks; pigs, 12 weeks; and monkeys, >104 weeks (Poletto et al., 2023). A single animal model that can recapitulate the entirety of human IVD degeneration remains to be established. However, the results can be interpreted reliably if the limitations of a selected animal species are recognized.

9 Clinical translation

Preclinical studies have demonstrated the promising results of regenerative disc therapies. Nevertheless, these therapies are associated with significant limitations that hinder their translation into clinical practice. These limitations include insufficient graft retention and integration into the disc space, limited survival and proliferation of the cells within the harsh disc microenvironment, uncontrolled differentiation of stem cells, mechanical instability of the implanted scaffolds, and concerns regarding long-term safety. Furthermore, the regulatory requirements for devices and biologics set forth by the U.S. Food and Drug Administration also pose hurdles. Clinical implementation of regenerative disc therapies requires optimization of cell sources, biomaterials, growth factors, PRP, gene therapy, mechanical stimulation, and delivery methods. Evaluation of clinically relevant models and personalized regenerative therapies tailored to individual patients can be achieved using biomarkers, advanced imaging modalities, and bioreactors.

10 Discussion

Preclinical studies on regenerative medicine therapies that utilize cells, biomaterials, growth factors, PRP, and biological agents have demonstrated their promise in repairing degenerated lumbar discs. However, these therapies are associated with significant limitations and challenges that hinder their clinical translation. Thus, further studies must be conducted in the future to address these challenges. Advances in the fields of tissue engineering, biomaterials, stem cells, and biological factors will facilitate regenerative therapies to halt or reverse progressive disc degeneration and improve the clinical outcomes and quality of life of patients with LDDD.

Author contributions

TSo: Conceptualization, Methodology, Project administration, Writing–original draft, Writing–review and editing. KS: Writing–original draft, Writing–review and editing, Conceptualization, Methodology, Project administration. TSh: Writing–review and editing, Writing–original draft, Supervision. KM: Writing–review and editing, Writing–original draft, Supervision. SM: Supervision, Writing–review and editing, Writing–original draft. BO: Supervision, Writing–review and editing, Writing–original draft.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
==== Refs
References

Ahrens M. Tsantrizos A. Donkersloot P. Martens F. Lauweryns P. Le Huec J. C. (2009). Nucleus replacement with the DASCOR disc arthroplasty device: interim two-year efficacy and safety results from two prospective, non-randomized multicenter European studies. Spine (Phila Pa 1976) 34 (13 ), 1376–1384. 10.1097/brs.0b013e3181a3967f 19440167
Akeda K. Ohishi K. Takegami N. Sudo T. Yamada J. Fujiwara T. (2022). Platelet-rich plasma releasate versus corticosteroid for the treatment of discogenic low back pain: a double-blind randomized controlled trial. J. Clin. Med. 11 (2 ), 304. 10.3390/jcm11020304 35053999
Akeda K. Yamada J. Linn E. T. Sudo A. Masuda K. (2019). Platelet-rich plasma in the management of chronic low back pain: a critical review. J. Pain Res. 12 , 753–767. 10.2147/JPR.S153085 30881089
Amirdelfan K. Bae H. McJunkin T. DePalma M. Kim K. Beckworth W. J. (2021). Allogeneic mesenchymal precursor cells treatment for chronic low back pain associated with degenerative disc disease: a prospective randomized, placebo-controlled 36-month study of safety and efficacy. Spine J. 21 (2 ), 212–230. 10.1016/j.spinee.2020.10.004 33045417
Beall D. P. Davis T. DePalma M. J. Amirdelfan K. Yoon E. S. Wilson G. L. (2021). Viable disc tissue allograft supplementation; one- and two-level treatment of degenerated intervertebral discs in patients with chronic discogenic low back pain: one year results of the VAST randomized controlled trial. Pain Physician 24 (6 ), 465–477.34554689
Berlemann U. Schwarzenbach O. (2009). An injectable nucleus replacement as an adjunct to microdiscectomy: 2 year follow-up in a pilot clinical study. Eur. Spine J. 18 (11 ), 1706–1712. 10.1007/s00586-009-1136-0 19688352
Bertagnoli R. Sabatino C. T. Edwards J. T. Gontarz G. A. Prewett A. Parsons J. R. (2005). Mechanical testing of a novel hydrogel nucleus replacement implant. Spine J. 5 (6 ), 672–681. 10.1016/j.spinee.2004.12.004 16363077
Bowles R. D. Gebhard H. H. Hartl R. Bonassar L. J. (2011). Tissue-engineered intervertebral discs produce new matrix, maintain disc height, and restore biomechanical function to the rodent spine. Proc. Natl. Acad. Sci. U S A. 108 (32 ), 13106–13111. 10.1073/pnas.1107094108 21808048
Bowles R. D. Setton L. A. (2017). Biomaterials for intervertebral disc regeneration and repair. Biomaterials 129 , 54–67. 10.1016/j.biomaterials.2017.03.013 28324865
Ceylan A. Asik I. Ozgencil G. E. Erken B. (2019). Clinical results of intradiscal hydrogel administration (GelStix) in lumbar degenerative disc disease. Turk J. Med. Sci. 49 (6 ), 1634–1639. 10.3906/sag-1901-1 31655507
Chaparro L. E. Furlan A. D. Deshpande A. Mailis-Gagnon A. Atlas S. Turk D. C. (2014). Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. Spine (Phila Pa 1976) 39 (7 ), 556–563. 10.1097/BRS.0000000000000249 24480962
Chik T. K. Chooi W. H. Li Y. Y. Ho F. C. Cheng H. W. Choy T. H. (2015). Bioengineering a multicomponent spinal motion segment construct--a 3D model for complex tissue engineering. Adv. Healthc. Mater 4 (1 ), 99–112. 10.1002/adhm.201400192 24846571
Choy A. T. Chan B. P. (2015). A structurally and functionally biomimetic biphasic scaffold for intervertebral disc tissue engineering. PLoS One 10 (6 ), e0131827. 10.1371/journal.pone.0131827 26115332
Clarke L. E. McConnell J. C. Sherratt M. J. Derby B. Richardson S. M. Hoyland J. A. (2014). Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs. Arthritis Res. Ther. 16 (2 ), R67. 10.1186/ar4505 24618041
Comella K. Silbert R. Parlo M. (2017). Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. J. Transl. Med. 15 (1 ), 12. 10.1186/s12967-016-1109-0 28086781
Coric D. Pettine K. Sumich A. Boltes M. O. (2013). Prospective study of disc repair with allogeneic chondrocytes presented at the 2012 Joint Spine Section Meeting. J. Neurosurg. Spine 18 (1 ), 85–95. 10.3171/2012.10.SPINE12512 23140128
de Queiroz B. Z. Pereira D. S. Lopes R. A. Felicio D. C. Silva J. P. Rosa N. M. (2016). Association between the plasma levels of mediators of inflammation with pain and disability in the elderly with acute low back pain: data from the back complaints in the elders (BACE)-Brazil study. Spine (Phila Pa 1976) 41 (3 ), 197–203. 10.1097/BRS.0000000000001214 26571172
Deyo R. A. Mirza S. K. (2016). Herniated lumbar intervertebral disk. N. Engl. J. Med. 374 (18 ), 1763–1772. 10.1056/NEJMcp1512658 27144851
Du J. Garcia J. P. Bach F. C. Tellegen A. R. Grad S. Li Z. (2022). Intradiscal injection of human recombinant BMP-4 does not reverse intervertebral disc degeneration induced by nuclectomy in sheep. J. Orthop. Transl. 37 , 23–36. 10.1016/j.jot.2022.08.006
Elabd C. Centeno C. J. Schultz J. R. Lutz G. Ichim T. Silva F. J. (2016). Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study. J. Transl. Med. 14 (1 ), 253. 10.1186/s12967-016-1015-5 27585696
Ellman M. B. Kim J. An H. S. Chen D. Kc R. Li X. (2013). Lactoferricin enhances BMP7-stimulated anabolic pathways in intervertebral disc cells. Gene 524 (2 ), 282–291. 10.1016/j.gene.2013.04.003 23644135
Fujii K. Yamazaki M. Kang J. D. Risbud M. V. Cho S. K. Qureshi S. A. (2019). Discogenic back pain: literature review of definition, diagnosis, and treatment. JBMR Plus 3 (5 ), e10180. 10.1002/jbm4.10180 31131347
Gantenbein-Ritter B. Benneker L. M. Alini M. Grad S. (2011). Differential response of human bone marrow stromal cells to either TGF-β1 or rhGDF-5. Eur. Spine J. 20 (6 ), 962–971. 10.1007/s00586-010-1619-z 21086000
Gay M. H. Mehrkens A. Rittmann M. Haug M. Barbero A. Martin I. (2019). Nose to back: compatibility of nasal chondrocytes with environmental conditions mimicking a degenerated intervertebral disc. Eur. Cell Mater 37 , 214–232. 10.22203/eCM.v037a13 30900738
Goode A. P. Marshall S. W. Kraus V. B. Renner J. B. Sturmer T. Carey T. S. (2012). Association between serum and urine biomarkers and lumbar spine individual radiographic features: the Johnston County Osteoarthritis Project. Osteoarthr. Cartil. 20 (11 ), 1286–1293. 10.1016/j.joca.2012.08.003
Goparaju P. Rajamani P. A. Kulkarni A. G. Kumar P. Adbalwad Y. M. Bhojraj S. (2023). A 2-year outcomes and complications of various techniques of lumbar discectomy: a multicentric prospective study. Glob. Spine J., 21925682231220042. 10.1177/21925682231220042
Gornet M. Buttermann G. Guyer R. Yue J. Ferko N. Hollmann S. (2017). Defining the ideal lumbar total disc replacement patient and standard of care. Spine (Phila Pa 1976) 42 (Suppl 24 ), S103–S107. 10.1097/BRS.0000000000002453 29176485
Haufe S. M. Mork A. R. (2006). Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev. 15 (1 ), 136–137. 10.1089/scd.2006.15.136 16522171
Hayden J. A. Ellis J. Ogilvie R. Malmivaara A. van Tulder M. W. (2021). Exercise therapy for chronic low back pain. Cochrane Database Syst. Rev. 9 (9 ), CD009790. 10.1002/14651858.CD009790.pub2 34580864
Henriksson H. B. Papadimitriou N. Hingert D. Baranto A. Lindahl A. Brisby H. (2019). The traceability of mesenchymal stromal cells after injection into degenerated discs in patients with low back pain. Stem Cells Dev. 28 (17 ), 1203–1211. 10.1089/scd.2019.0074 31237488
Hiraishi S. Schol J. Sakai D. Nukaga T. Erickson I. Silverman L. (2018). Discogenic cell transplantation directly from a cryopreserved state in an induced intervertebral disc degeneration canine model. JOR Spine 1 (2 ), e1013. 10.1002/jsp2.1013 31463441
Iatridis J. C. Nicoll S. B. Michalek A. J. Walter B. A. Gupta M. S. (2013). Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair? Spine J. 13 (3 ), 243–262. 10.1016/j.spinee.2012.12.002 23369494
Kamatani T. Hagizawa H. Yarimitsu S. Morioka M. Koyamatsu S. Sugimoto M. (2022). Human iPS cell-derived cartilaginous tissue spatially and functionally replaces nucleus pulposus. Biomaterials 284 , 121491. 10.1016/j.biomaterials.2022.121491 35395453
Kato K. Akeda K. Miyazaki S. Yamada J. Muehleman C. Miyamoto K. (2021). NF-kB decoy oligodeoxynucleotide preserves disc height in a rabbit anular-puncture model and reduces pain induction in a rat xenograft-radiculopathy model. Eur. Cell Mater 42 , 90–109. 10.22203/eCM.v042a07 34284523
Kent P. Haines T. O'Sullivan P. Smith A. Campbell A. Schutze R. (2023). Cognitive functional therapy with or without movement sensor biofeedback versus usual care for chronic, disabling low back pain (RESTORE): a randomised, controlled, three-arm, parallel group, phase 3, clinical trial. Lancet 401 (10391 ), 1866–1877. 10.1016/S0140-6736(23)00441-5 37146623
Khan A. N. Jacobsen H. E. Khan J. Filippi C. G. Levine M. Lehman R. A. Jr (2017). Inflammatory biomarkers of low back pain and disc degeneration: a review. Ann. N Y Acad. Sci. 1410 (1 ), 68–84. 10.1111/nyas.13551 29265416
Koetsier E. van Kuijk S. M. J. Maino P. Dukanac J. Scascighini L. Cianfoni A. (2022). Efficacy of the Gelstix nucleus augmentation device for the treatment of chronic discogenic low back pain: protocol for a randomised, sham-controlled, double-blind, multicentre trial. BMJ Open 12 (3 ), e053772. 10.1136/bmjopen-2021-053772
Kumar H. Ha D. H. Lee E. J. Park J. H. Shim J. H. Ahn T. K. (2017). Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res. Ther. 8 (1 ), 262. 10.1186/s13287-017-0710-3 29141662
Lewandrowski K. U. Dowling A. Vera J. C. Leon J. F. R. Telfeian A. E. Lorio M. P. (2023). Pain relief after allogenic stem cell disc therapy. Pain Physician 26 (2 ), 197–206.36988365
Li Y. Chen L. Gao Y. Zou X. Wei F. (2022). Oxidative stress and intervertebral disc degeneration: pathophysiology, signaling pathway, and therapy. Oxid. Med. Cell Longev. 2022 , 1–14. 10.1155/2022/1984742
Martin J. T. Milby A. H. Chiaro J. A. Kim D. H. Hebela N. M. Smith L. J. (2014). Translation of an engineered nanofibrous disc-like angle-ply structure for intervertebral disc replacement in a small animal model. Acta Biomater. 10 (6 ), 2473–2481. 10.1016/j.actbio.2014.02.024 24560621
Matta A. Karim M. Z. Gerami H. Jun P. Funabashi M. Kawchuk G. (2018). NTG-101: a novel molecular therapy that halts the progression of degenerative disc disease. Sci. Rep. 8 (1 ), 16809. 10.1038/s41598-018-35011-4 30429487
Mehrkens A. Muller A. M. Valderrabano V. Scharen S. Vavken P. (2012). Tissue engineering approaches to degenerative disc disease--a meta-analysis of controlled animal trials. Osteoarthr. Cartil. 20 (11 ), 1316–1325. 10.1016/j.joca.2012.06.001
Miyazaki S. Diwan A. D. Kato K. Cheng K. Bae W. C. Sun Y. (2018). ISSLS PRIZE IN BASIC SCIENCE 2018: growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model. Eur. Spine J. 27 (4 ), 739–751. 10.1007/s00586-018-5488-1 29460012
Mizuno H. Roy A. K. Zaporojan V. Vacanti C. A. Ueda M. Bonassar L. J. (2006). Biomechanical and biochemical characterization of composite tissue-engineered intervertebral discs. Biomaterials 27 (3 ), 362–370. 10.1016/j.biomaterials.2005.06.042 16165204
Mochida J. Sakai D. Nakamura Y. Watanabe T. Yamamoto Y. Kato S. (2015). Intervertebral disc repair with activated nucleus pulposus cell transplantation: a three-year, prospective clinical study of its safety. Eur. Cell Mater 29 , 202–212. ; discussion 12. 10.22203/ecm.v029a15 25794529
Nerurkar N. L. Sen S. Huang A. H. Elliott D. M. Mauck R. L. (2010). Engineered disc-like angle-ply structures for intervertebral disc replacement. Spine (Phila Pa 1976) 35 (8 ), 867–873. 10.1097/BRS.0b013e3181d74414 20354467
Nesti L. J. Li W. J. Shanti R. M. Jiang Y. J. Jackson W. Freedman B. A. (2008). Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng. Part A 14 (9 ), 1527–1537. 10.1089/ten.tea.2008.0215 18707229
Noriega D. C. Ardura F. Hernandez-Ramajo R. Martin-Ferrero M. A. Sanchez-Lite I. Toribio B. (2017). Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation 101 (8 ), 1945–1951. 10.1097/TP.0000000000001484 27661661
Nukaga T. Sakai D. Schol J. Sato M. Watanabe M. (2019). Annulus fibrosus cell sheets limit disc degeneration in a rat annulus fibrosus injury model. JOR Spine 2 (2 ), e1050. 10.1002/jsp2.1050 31463464
Ohnishi T. Sudo H. Tsujimoto T. Iwasaki N. (2018). Age-related spontaneous lumbar intervertebral disc degeneration in a mouse model. J. Orthop. Res. 36 (1 ), 224–232. 10.1002/jor.23634 28631843
Ohtori S. Inoue G. Miyagi M. Takahashi K. (2015). Pathomechanisms of discogenic low back pain in humans and animal models. Spine J. 15 (6 ), 1347–1355. 10.1016/j.spinee.2013.07.490 24657737
Oichi T. Taniguchi Y. Oshima Y. Tanaka S. Saito T. (2020). Pathomechanism of intervertebral disc degeneration. JOR Spine 3 (1 ), e1076. 10.1002/jsp2.1076 32211588
Orozco L. Soler R. Morera C. Alberca M. Sanchez A. Garcia-Sancho J. (2011). Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92 (7 ), 822–828. 10.1097/TP.0b013e3182298a15 21792091
Osada R. Ohshima H. Ishihara H. Yudoh K. Sakai K. Matsui H. (1996). Autocrine/paracrine mechanism of insulin-like growth factor-1 secretion, and the effect of insulin-like growth factor-1 on proteoglycan synthesis in bovine intervertebral discs. J. Orthop. Res. 14 (5 ), 690–699. 10.1002/jor.1100140503 8893760
Otsuki B. Fujibayashi S. Shimizu T. Murata K. Masuda S. Matsuda S. (2023). Minimally invasive LLIF surgery to decrease the occurrence of adjacent-segment disease compared to conventional open TLIF. Eur. Spine J. 32 (9 ), 3200–3209. 10.1007/s00586-023-07806-1 37314580
Özer M. İ. Demirtaş O. K. (2023). Comparison of lumbar microdiscectomy and unilateral biportal endoscopic discectomy outcomes: a single-center experience. J. Neurosurg. Spine 40 (3 ), 351–358. 10.3171/2023.10.SPINE23718 38064698
Pang X. Yang H. Peng B. (2014). Human umbilical cord mesenchymal stem cell transplantation for the treatment of chronic discogenic low back pain. Pain Physician 17 (4 ), E525–E530.25054402
Park H. J. Lee C. S. Chung S. S. Park S. J. Kim W. S. Park J. S. (2018). Radiological and clinical long-term results of heterotopic ossification following lumbar total disc replacement. Spine J. 18 (5 ), 762–768. 10.1016/j.spinee.2017.09.003 28939171
Park S. H. Gil E. S. Cho H. Mandal B. B. Tien L. W. Min B. H. (2012). Intervertebral disk tissue engineering using biphasic silk composite scaffolds. Tissue Eng. Part A 18 (5-6 ), 447–458. 10.1089/ten.TEA.2011.0195 21919790
Pelletier M. H. Cohen C. S. Ducheyne P. Walsh W. R. (2016). Restoring segmental biomechanics through nucleus augmentation: an in vitro study. Clin. Spine Surg. 29 (10 ), 461–467. 10.1097/bsd.0b013e3182aa6841 24141339
Pettine K. A. Murphy M. B. Suzuki R. K. Sand T. T. (2015). Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells 33 (1 ), 146–156. 10.1002/stem.1845 25187512
Poletto D. L. Crowley J. D. Tanglay O. Walsh W. R. Pelletier M. H. (2023). Preclinical in vivo animal models of intervertebral disc degeneration. Part 1: a systematic review. JOR Spine 6 (1 ), e1234. 10.1002/jsp2.1234 36994459
Ray C. D. (2002). The PDN® prosthetic disc-nucleus device. Eur. Spine J. 11 (2 ), S137–S142. 10.1007/s00586-002-0425-7 12384735
Risbud M. V. Di Martino A. Guttapalli A. Seghatoleslami R. Denaro V. Vaccaro A. R. (2006). Toward an optimum system for intervertebral disc organ culture: TGF-beta 3 enhances nucleus pulposus and anulus fibrosus survival and function through modulation of TGF-beta-R expression and ERK signaling. Spine (Phila Pa 1976) 31 (8 ), 884–890. 10.1097/01.brs.0000209335.57767.b5 16622376
Sainoh T. Orita S. Miyagi M. Inoue G. Kamoda H. Ishikawa T. (2016). Single intradiscal administration of the tumor necrosis factor-alpha inhibitor, etanercept, for patients with discogenic low back pain. Pain Med. 17 (1 ), 40–45. 10.1111/pme.12892 26243249
Sakai D. Andersson G. B. (2015). Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nat. Rev. Rheumatol. 11 (4 ), 243–256. 10.1038/nrrheum.2015.13 25708497
Sakai D. Mochida J. Iwashina T. Hiyama A. Omi H. Imai M. (2006). Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 27 (3 ), 335–345. 10.1016/j.biomaterials.2005.06.038 16112726
Sakai D. Schol J. Watanabe M. (2022). Clinical development of regenerative medicine targeted for intervertebral disc disease. Med. Kaunas. 58 (2 ), 267. 10.3390/medicina58020267
Sheyn D. Ben-David S. Tawackoli W. Zhou Z. Salehi K. Bez M. (2019). Human iPSCs can be differentiated into notochordal cells that reduce intervertebral disc degeneration in a porcine model. Theranostics 9 (25 ), 7506–7524. 10.7150/thno.34898 31695783
Shimizu T. Fujibayashi S. Otsuki B. Murata K. Matsuda S. (2021). Indirect decompression via oblique lateral interbody fusion for severe degenerative lumbar spinal stenosis: a comparative study with direct decompression transforaminal/posterior lumbar interbody fusion. Spine J. 21 (6 ), 963–971. 10.1016/j.spinee.2021.01.025 33540124
Siepe C. J. Heider F. Wiechert K. Hitzl W. Ishak B. Mayer M. H. (2014). Mid-to long-term results of total lumbar disc replacement: a prospective analysis with 5- to 10-year follow-up. Spine J. 14 (8 ), 1417–1431. 10.1016/j.spinee.2013.08.028 24448028
Stürmer T. Raum E. Buchner M. Gebhardt K. Schiltenwolf M. Richter W. (2005). Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain. Ann. Rheum. Dis. 64 (6 ), 921–925. 10.1136/ard.2004.027045 15897311
Sun B. Lian M. Han Y. Mo X. Jiang W. Qiao Z. (2020)). A 3D-Bioprinted dual growth factor-releasing intervertebral disc scaffold induces nucleus pulposus and annulus fibrosus reconstruction. Bioact. Mater 6 (1 ), 179–190. 10.1016/j.bioactmat.2020.06.022 32913927
Sun R. Zhu J. Sun K. Gao L. Zheng B. Shi J. (2023). Strontium ranelate ameliorates intervertebral disc degeneration via regulating TGF-β1/NF-κB Axis. Int. J. Med. Sci. 20 (13 ), 1679–1697. 10.7150/ijms.86665 37928874
Tim Y. S. Su Kim K. Li J. Soo Park J. Akamaru T. Elmer W. A. (2003). The effect of bone morphogenetic protein-2 on rat intervertebral disc cells in vitro . Spine (Phila Pa 1976) 28 (16 ), 1773–1780. 10.1097/01.BRS.0000083204.44190.34 12923462
Tsai T. T. Guttapalli A. Oguz E. Chen L. H. Vaccaro A. R. Albert T. J. (2007). Fibroblast growth factor-2 maintains the differentiation potential of nucleus pulposus cells in vitro: implications for cell-based transplantation therapy. Spine (Phila Pa 1976) 32 (5 ), 495–502. 10.1097/01.brs.0000257341.88880.f1 17334282
Tsantrizos A. Ordway N. R. Myint K. Martz E. Yuan H. A. (2008). Mechanical and biomechanical characterization of a polyurethane nucleus replacement device injected and cured in situ within a balloon. SAS J. 2 (1 ), 28–39. 10.1016/sasj-2007-0113-rr 25802599
Tschugg A. Diepers M. Simone S. Michnacs F. Quirbach S. Strowitzki M. (2017). A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of Phase I-a short report. Neurosurg. Rev. 40 (1 ), 155–162. 10.1007/s10143-016-0781-0 27567635
Tuakli-Wosornu Y. A. Terry A. Boachie-Adjei K. Harrison J. R. Gribbin C. K. LaSalle E. E. (2016). Lumbar intradiskal platelet-rich plasma (PRP) injections: a prospective, double-blind, randomized controlled study. PM R. 8 (1 ), 1–10. 10.1016/j.pmrj.2015.08.010 26314234
Ukeba D. Yamada K. Tsujimoto T. Ura K. Nonoyama T. Iwasaki N. (2021). Bone marrow aspirate concentrate combined with in situ forming bioresorbable gel enhances intervertebral disc regeneration in rabbits. J. Bone Jt. Surg. Am. 103 (8 ), e31. 10.2106/JBJS.20.00606
van den Eerenbeemt K. D. Ostelo R. W. van Royen B. J. Peul W. C. van Tulder M. W. (2010). Total disc replacement surgery for symptomatic degenerative lumbar disc disease: a systematic review of the literature. Eur. Spine J. 19 (8 ), 1262–1280. 10.1007/s00586-010-1445-3 20508954
Wang D. Lai A. Gansau J. Seifert A. C. Munitz J. Zaheer K. (2023). Lumbar endplate microfracture injury induces Modic-like changes, intervertebral disc degeneration and spinal cord sensitization - an in vivo rat model. Spine J. 23 (9 ), 1375–1388. 10.1016/j.spinee.2023.04.012 37086976
Wang H. Ahrens C. Rief W. Gantz S. Schiltenwolf M. Richter W. (2010). Influence of depression symptoms on serum tumour necrosis factor-alpha of patients with chronic low back pain. Arthritis Res. Ther. 12 (5 ), R186. 10.1186/ar3156 20937109
Wei Q. Liu D. Chu G. Yu Q. Liu Z. Li J. (2022). TGF-β1-supplemented decellularized annulus fibrosus matrix hydrogels promote annulus fibrosus repair. Bioact. Mater 19 (19 ), 581–593. 10.1016/j.bioactmat.2022.04.025 35600980
Weiss A. R. R. Dahlke M. H. (2019). Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front. Immunol. 10 , 1191. 10.3389/fimmu.2019.01191 31214172
Yuksel U. Walsh S. Curd D. Black K. (2002). Fatigue durabiity of a novel disc nucleus repair system. Spine J. 2 (5 ), 103–104. 10.1016/S1529-9430(02)00233-4
Zhang Y. Zhang Z. Chen P. Ma C. Y. Li C. Au T. Y. K. (2020). Directed differentiation of notochord-like and nucleus pulposus-like cells using human pluripotent stem cells. Cell Rep. 30 (8 ), 2791–2806 e5. 10.1016/j.celrep.2020.01.100 32101752
Zhuang Y. Huang B. Li C. Q. Liu L. T. Pan Y. Zheng W. J. (2011). Construction of tissue-engineered composite intervertebral disc and preliminary morphological and biochemical evaluation. Biochem. Biophys. Res. Commun. 407 (2 ), 327–332. 10.1016/j.bbrc.2011.03.015 21382343
