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. Author manuscript; available in PMC: 2025 Aug 13.
Published in final edited form as: World Neurosurg. 2025 Jun 2;199:124132. doi: 10.1016/j.wneu.2025.124132

Bioactive Therapies for Degenerative Disc Disease: Challenges and Innovations

Alikhan B Fidai 1, Ashley Cardenas 1, Chibuikem A Ikwuegbuenyi 2, Anthony Robayo 2, Noah Willett 2, Ibrahim Hussain 2, Roger Härtl 2, Lawrence J Bonassar 1,3
PMCID: PMC12344652  NIHMSID: NIHMS2098838  PMID: 40561644

INTRODUCTION

Over the past 2 decades, several advancements in bioactive therapies have aimed to promote long-term healing and restore the native function of intervertebral discs (IVDs). Bioactive therapies for disc degeneration utilize a combination of cells, biomaterials, and soluble factors to enhance the body’s natural capacity for disc repair and regeneration.1–4 These therapies target multiple clinically relevant presentations of disc disease, including early-stage degeneration, herniation, and end-stage degeneration. This article is the third in a three-part series. In the first part of this series,5 we explored microenvironmental changes across all three clinically relevant presentations of disc disease. In the second part of this series,6 we reviewed clinically available and state-of-the-art treatments for degenerative disc disease. In this final part of this series, we discuss challenges and innovations in bioactive therapies for disc degeneration. Although several challenges arise in the utilization of cells and engineered tissues, innovations in bioactive and cell-based therapies hold great promise and provide a roadmap for translating these technologies for disc repair.

EARLY-STAGE DEGENERATION

In early-stage degeneration, the IVD microenvironment is subjected to inflammation, cellular apoptosis, mitochondrial dysfunction, and catabolic factors. Recent innovations in bioactive therapies for early-stage disc degeneration leverage the regenerative potential of mesenchymal stem cells (MSCs) to promote tissue regeneration and halt the progression of disc disease. MSCs are multipotent cells with the capacity to differentiate into osteogenic, chondrogenic, and adipogenic lineages. The regenerative capacity of MSCs from different tissue sources has been tested in several in vitro and in vivo model systems. Recent works have also harnessed the restorative potential of secreted factors and MSC mitochondria to promote extracellular matrix (ECM) repair and restore the bioenergetics of resident disc cells. Ultimately, these studies motivated research on MSC genome editing to further enhance matrix synthesis and cell survivability in the biologically challenging degenerative microenvironment. Altogether, MSCs remain a highly potent cell type for responding to microenvironmental changes in early-stage disc degeneration.

MSC Characterization and Localization

The criteria for what constitutes an MSC are highly specific. The International Society for Cellular Therapies has outlined three minimum criteria for classifying MSCs.7 First, MSCs must be plastic adherent. Second, MSCs must express CD73, CD90, and CD105 and lack expression of CD14, CD19, CD34, and CD45. Third, MSCs must possess trilineage differentiation potential. After the identification of MSCs in the 1990s, the field initially believed that the main mechanism they employed to aid in disc repair was by differentiating into IVD-like cells.8 Differentiation into any of these cell types is a tightly regulated process that takes several weeks.9 However, leakage of MSCs from the disc and cell death following transplantation remain challenges.10–12 To elucidate the regenerative potential of MSCs, various groups have established in vitro and in vivo model systems to interrogate the cells’ capacity to resolve inflammation and promote matrix synthesis.

Interrogating the Regenerative Potential of MSCs

MSCs can be readily isolated from bone marrow, adipose tissue, and umbilical cord tissue. Although MSCs reside in multiple tissues, their efficacy for enhancing cell survival, resolving inflammation, promoting matrix synthesis, and regulating the balance of catabolic and anabolic factors is consistent across tissue sources. In vitro studies demonstrate that coculturing bone marrow MSCs with nucleus pulposus (NP) cells can delay matrix degeneration by upregulating transforming growth factor beta (TGF-β) and reducing inflammation through the nuclear factor–κB pathway.13 Similarly, one study demonstrated that coculturing adipose tissue–derived stem cells with NP cells upregulated aggrecan expression, further supporting ECM stability.14 Another study found that co-culturing umbilical cord stem cells and NP cells on polyethylene glycol scaffolds promoted differentiation of the stem cells into NP-like cells.15 Interestingly, these umbilical cord stem cell–laden scaffolds promoted greater glycosaminoglycan synthesis in an ex vivo degenerative rabbit model.15 To holistically assess the efficacy of MSC-based therapies, several groups have employed various animal models. Delivery of bone marrow MSCs was found to improve disc height, cell survival, and proteoglycan synthesis in an ex vivo bovine organ culture.16 Moreover, studies in rats and canines demonstrated that intradiscal delivery of adipose tissue–derived stem cells attenuated disc degeneration and enhanced ECM production.17,18 Similarly, intradiscal delivery of human umbilical cord–derived stem cells delayed disc height decline and promoted aggrecan and type II collagen production in degenerative canine IVDs.19 Although many of these studies did not enhance cell retention, they still demonstrated a therapeutic benefit from MSC delivery. Thus, differentiation into IVD-like cells is likely not the mechanism employed by MSCs to aid disc repair.

MSC-Derived Exosomes

Instead of repopulating damaged discs with differentiated cells, MSCs use paracrine signaling to identify distressed cells and rescue these cells via the MSC secretome.20 The secretome is a collection of secreted cytokines, chemokines, growth factors, exosomes, and microvesicles containing proteins and microRNAs to aid in cell-cell communication.21 Several studies have demonstrated that delivering MSC-derived exosomes (MSC-Exos) containing microRNAs, such as miR-21,22 miR-142–3p,23 and miR-26a-5p,24 enhanced NP cell survival and ameliorated disc degeneration. To promote endogenous annulus fibrosus (AF) repair, DiStefano et al. encapsulated MSC-Exos in poly(lactic-co-glycolic acid) (PLGA) for sustained delivery (Figure 1).25 AF cells treated with MSC-Exos collected from MSCs cultured under hypoxic conditions yielded favorable outcomes, imparting a protective effect against inflammatory cytokines. Similarly, Yang and Yang demonstrated that treatment with MSC-Exos suppressed inflammation in a rat model of IVD degeneration and reversed the expression of interleukin 6 (IL-6), IL-1β, and tumor necrosis factor alpha.26 Results from these studies have motivated rigorous characterization of MSC-Exos to determine what is driving tissue regeneration. Surprisingly, recent work (discussed in the next section) has revealed that MSCs are capable of shuttling their own organelles to rescue distressed disc cells.

Figure 1.

Figure 1.

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Bioactive therapies for multiple clinically relevant presentations of disc degeneration. AF, annulus fibrosus; IVD, intervertebral disc; MSC, mesenchymal stem cell; NP, nucleus pulposus; UV, ultraviolet. Images in the panels on the left side of the figure were created with Biorender.com.

Mitochondrial Therapies

In the last 5 years, researchers have been exploring a novel mechanism employed by MSCs to rescue the bioenergetics of recipient cells: mitochondrial transfer.27,28 In the degenerative state, IVD cells possess dysfunctional mitochondria, leading to the accumulation of harmful reactive oxygen species and ultimately cellular senescence.29 Donation of mitochondria from MSCs to NP cells has been shown to restore mitochondrial membrane potential and prevent apoptosis.30 Moreover, mitochondrial dysfunction is an acute response to mechanical injury. One study demonstrated that rapid impact injury to articular cartilage explants led to mitochondrial dysfunction within chondrocytes.31 To ameliorate the effects of impact injury, later studies treated impacted samples with SS-31, a mitoprotective peptide that preserves the structure of the inner mitochondrial membrane.32,33 These studies demonstrated that treatment with SS-31 preserved chondrocyte viability, enhanced mitochondrial function, and prevented further degeneration. A similar study investigated the effects of treating NP cells with mitoprotective peptides. Interestingly, treatment with SS-31 attenuated lipopolysaccharide-induced apoptosis of NP cells and inhibited activation of the nuclear factor–κB pathway.34 Although treatment with mitoprotective peptides restored mitochondrial function, research efforts toward engineering cell populations to enhance their survivability in the degenerative microenvironment have gained interest.

Gene Editing for IVD Repair

The avascular, nutrient-deficient, and acidic microenvironment of the degenerative IVD poses a challenging milieu for transplanted cells to enhance repair and regeneration.35 For this reason, recent advancements in cell engineering have leveraged clustered regularly interspaced short palindromic repeats (CRISPR) technology to target key DNA sequences, promote matrix synthesis, and enhance cell survival (Figure 1).36,37 One study demonstrated that CRISPR/Cas9 activation of ACAN and COL2A1 resulted in increased aggrecan and collagen II deposition from adipose tissue–derived stem cells.38 Further studies engineered adipose tissue–derived stem cells to enhance their survivability in acidic and inflammatory environments.39,40 Results from these studies were promising and prompted the investigation of incorporating CRISPR-edited cells with enhanced ECM deposition and reduced cellular senescence in composite tissue-engineered IVDs for total disc replacement.41 Altogether, CRISPR/Cas9 is a promising and innovative tool for enhancing the efficacy of transplanted cells in the degenerative IVD microenvironment and may lead to improved outcomes for total disc replacement.

Another method for engineering cells for IVD repair is via lentiviral vectors. One study investigated the effects of intradiscally injecting lentivirus to knock down MMP3 and overexpress SOX9 in a rabbit model.42 Results from this study indicate that MMP3 knockdown and SOX9 overexpression substantially inhibited the progression of disc degeneration and stimulated ECM synthesis in disc cells. Similarly, another study performed lentivirus-mediated TGF-β3, CTGF, and TIMP1 gene transduction in an in vivo rabbit model.43 Interestingly, cotransduction of TGF-β3, CTGF, and TIMP1 significantly enhanced aggrecan and type II collagen production in degenerative discs. Collectively, gene editing technology remains a promising and exciting innovation for enhancing the survivability of transplanted cells in the degenerative microenvironment.

HERNIATION

Disc degeneration is accompanied by the progressive depletion of ECM components responsible for imparting osmotic pressure and resiliency to cyclic loading.44 Consequently, the degenerative IVD undergoes dehydration and is far more susceptible to weakening, annular tears, and herniation.45 The most common surgical approach for treating lumbar disc herniation is discectomy, in which extruded or bulging NP tissue is surgically removed. Although discectomy leads to a significant decrease in patient-reported pain and disability,46,47 discectomy alone does not promote long-term healing at the site of herniation. Results from a 2-year prospective cohort study demonstrated that 23.1% of patients who underwent lumbar discectomy had radiographic evidence of recurrent same-site disc herniation.48 In order to address these challenges, researchers have developed acellular and cellular adhesive hydrogels to seal annular defects and mitigate the risk of reherniation. Moreover, a new method for sustained drug delivery and mechanical augmentation at the herniation site provides new insights on promoting long-term healing.

Adhesive Hydrogels for Herniation Repair

The extrusion of NP tissue through annular defects leaves the IVD susceptible to further damage and degeneration,49 and several studies have utilized adhesive hydrogels to seal these defects. The first in vivo study to test an injectable adhesive hydrogel engineered a riboflavin cross-linked high-density collagen (HDC) gel to seal annular defects in a needle-punctured rat-tail model.50 Cross-linking the collagen gel significantly improved water retention and disc height maintenance when compared to noncross-linked and punctured controls. Continuations of this study investigated the effects of HDC treatment on disc mechanics via an in vitro rat tail model and found that HDC-treated discs exhibited 95% of undamaged effective equilibrium and instantaneous moduli.51 Interestingly, HDC treatment inhibited the progression of disc degeneration for up to 18 weeks in vivo and histological examination demonstrated early tight attachment of the gel to annular defects in a needle-punctured rat-tail model.52 Another study investigated a combined treatment consisting of NP and AF repair in an ex vivo rat-tail nucleotomy model.53 Combined NP and AF repair maintained native disc hydration and restored NP morphology via. Results from this study demonstrate that composite NP and AF repair systems are superior to annular repair alone. To test the functionality of composite repair systems in a large animal model, related studies treated punctured IVDs with an HDC patch or with a hyaluronic acid injection followed by an HDC patch in an ovine model.54,55 These studies demonstrated that combined treatment consisting of NP augmentation and annular repair maintained native NP hydration and native torsional and compressive stiffnesses for up to 6 weeks in the lumbar spine. Another method for herniation repair utilizes a fibrin-genipin adhesive hydrogel to seal annular defects. One study in an ex vivo organ culture model found that fibrin-genipin filled annular defects and maintained both disc height and hydration.56 Continuations of this study developed unique composite hydrogel repair systems and demonstrated that combined treatment via NP augmentation and AF sealant enhanced integration with annular defects.57,58 Although herniation repair via adhesive hydrogels has shown great success in various animal models, persistent repair is difficult to achieve without cells.

Cellular Hydrogels for Herniation

To achieve persistent repair, herniation therapies must improve ECM deposition and remodeling.59 Including cells in these repair strategies would provide the machinery needed to respond to biomechanical and biochemical cues in the degenerative IVD, and recent work has included AF cells or MSCs in biomaterial scaffolds. In one study, AF cells were encapsulated in a photocross-linked HDC gel for annular repair in a needle-punctured rat-tail model (Figure 1).60 Results from this study demonstrated that repair with the AF-collagen gel significantly improved disc height when compared to discectomy alone. Moreover, the AF-collagen gel significantly improved the retention of tissue hydration when compared to discectomy or treatment with an acellular collagen gel. To test the efficacy of cellular hydrogels under biomechanically relevant loading, a study from the same group evaluated MSCs encapsulated in an HDC gel for annular repair in an ovine model.61 Treatment with the MSC-seeded gel improved disc height maintenance and water retention when compared to an acellular gel or discectomy control. Collectively, these studies demonstrate that cellular hydrogels may enhance herniation repair when compared to acellular repair or discectomy alone.

Mechanical Augmentation and Drug Delivery for Herniation Repair

Bioactive therapies utilizing biomaterials, cells, soluble factors, and novel engineering approaches have gained traction as means to restore native disc structure, composition, and mechanical function following IVD herniation. A recent study engineered tension-activated nanofiber patches (TARPs) composed of electrospun layers of poly(caprolactone) and poly(ethylene oxide).62 In this study, TARPs were embedded with mechanically activated microcapsules containing the IL-1β receptor antagonist, anakinra. IL-1β is an inflammatory cytokine that increases the expression of catabolic matrix-degrading enzymes and signals for the recruitment of immune cells.63 Results from this study demonstrated that TARPs remained in place for 4 weeks in the goat cervical spine, leading to robust integration and ECM deposition. Anakinra delivery at the injury site led to improved infiltration of repair tissue and preservation of the AF/NP border. Collectively, this repair strategy combines both mechanical and bioactive repair to enhance long-term healing in herniated discs and prevent further extrusion of disc tissue.

END-STAGE DEGENERATION

End-stage disc degeneration is characterized by a severe collapse of disc height, resulting in near-complete loss of tissue hydration and disruption of the vertebral endplates. Clinically available treatments for end-stage degeneration aim to restore disc height or replicate native IVD mechanics. Interbody approaches, such as those used in anterior cervical discectomy and fusion and transforaminal lumbar interbody fusion, utilize a structural implant made of titanium, polyetheretherketone, or cadaveric bone to replace the IVD. These are usually combined with titanium plates, screws, and rods to fix adjacent vertebrae. Although fusion rates for anterior cervical discectomy and fusion and transforaminal lumbar interbody fusion surgeries are well-documented,64–67 these treatments fail to restore native disc hydration and architecture. Moreover, these procedures are prone to various failure modes, including nonunion, subsidence, screw loosening, and infection.68–71 Artificial disc replacement, where implants do not require supplemental fixation, has limited indications in cases where there is end-stage disc degeneration and concomitant malalignment, facet arthropathy, or severe collapse.72 As a solution, researchers have developed composite tissue-engineered intervertebral discs (TE-IVDs) for total disc replacement. The efficacy of TE-IVDs has been tested in small and large animal models with promising results.

Composite TE-IVD Development and Testing in Small-Animal Models

Composite TE-IVDs are composed of cell-laden biomaterials and scaffolds that recapitulate the inner NP and outer AF (Figure 1). The first composite TE-IVD comprised an NP cell–seeded alginate core surrounded by an AF cell–seeded polyglycolic acid scaffold. These TE-IVDs were implanted subcutaneously in athymic mice and demonstrated a striking histological, biochemical, and mechanical similarity to native disc.73,74 Continuations of these studies sought to test the efficacy of TE-IVDs in the avascular and nutrient-deficient IVD microenvironment, implanting TE-IVDs in the caudal and lumbar spines of rats. Interestingly, histology revealed that these TE-IVDs integrated well with adjacent vertebrae.75,76 Moreover, the implants remained in the caudal and lumbar spines for 6 months, demonstrating the long-term viability of TE-IVDs in the biologically challenging IVD microenvironment. In another study, Gullbrand et al. implanted composite endplate-modified disc-like angle-ply structures (DAPS) composed of an NP cell-seeded agarose core surrounded by concentric layers of AF cell-seeded PCL nanofibers in the rat caudal spine.76 The DAPS remained in the spine for up to 20 weeks, with compressive mechanics reaching native values at the study endpoint. Despite the notable success of these studies, they did not subject the TE-IVDs to relevant mechanical loading.

Composite TE-IVDs in Large Animal Models

In order to test the functionality of TE-IVDs under physiologically relevant loading, studies in large animal models have been undertaken. In one study, composite TE-IVDs were implanted in the canine cervical spine for up to 16 weeks.77 This study demonstrated that stably implanted TE-IVDs maintained their structure, hydration, disc height, and integration with neighboring vertebrae until the study endpoint. However, displacement occurred following distraction release in half of these implants, highlighting the need for fixation of TE-IVDs following implantation. To evaluate their endplate-modified DAPS in a large-animal model, Gullbrand et al. implanted larger constructs in the goat cervical spine.78 To enhance retention, titanium fixation plates were used at the site of implantation. The DAPS maintained their composition and structure for 8 weeks in vivo, demonstrating compressive mechanics that matched native disc tissue. Although the titanium plates prevented implant displacement, it should be noted that in the clinical setting removal of such fixation plates following integration would necessitate revision surgery. Another study tested the efficacy of a resorbable PLGA plating system to enhance implant retention ex vivo in the canine cervical spine.79 An optimal resorbable plating system would degrade at a timescale that would enable implant integration without requiring surgical removal. Interestingly, fixation with a PLGA plating system prevented implant displacement, improved disc height maintenance, and enhanced the compressive stiffness of treated levels. Both of these systems enhanced implant retention, and a key feature shared between them is that they utilized stiffer materials to mechanically augment TE-IVDs. Although stiffer materials are well-suited for transmitting vertebral loads, they undergo various failure modes in the highly dynamic IVD microenvironment. In a recent study, TE-IVDs were mechanically augmented with cages composed of FlexiFil (FormFutura, Nijmegen, the Netherlands), a flexible support material, for 6 weeks in the minipig cervical spine.80 This study demonstrated FlexiFil cages outperformed traditional poly(lactic acid) cages by restoring native disc height and supporting the formation of hydrated tissues in vivo. Moreover, FlexiFil cages resisted microscale damage from indentation and prevented the delamination of print layers when compared to poly(lactic acid). Overall, this study highlighted the importance of selecting a flexible material for mechanically supporting TE-IVDs in vivo.

To summarize, a variety of in vivo models have been used to screen TE-IVDs, including small animals such as mice and rats, as well as larger animals such as pigs, dogs, and goats. Small animals allow for a greater number of studies but represent mechanical environments that are quite different from the human spine. Large animals provide aspects of the mechanical environment (e.g., intradiscal pressure) that are quite similar to those of humans but are far more expensive, and hence more difficult to study at scale.

FUTURE OUTLOOKS

Despite notable advantages in engineering bioactive therapies for disc degeneration, significant work is needed to translate these therapies from the bench top to the bedside. There are a vast number of factors that influence long-term healing and tissue regeneration, and future outlooks for bioactive therapies must leverage novel tools and assays to characterize the complex milieu of the degenerative IVD.

Spatial transcriptomics is a recently developed technique that provides spatially resolved genetic sequencing data of heterogeneous tissues like the IVD.81 A recent study used spatial transcriptomics to characterize NP progenitor cells and develop the first spatial transcriptomic map of the mouse IVD.82 Findings from this study suggest that a small number of cathepsin K-expressing cells develop into the entire NP in adult mice. Altogether, this study generates a spatially resolved profile of gene expression that would enable further investigation of interactions between NP progenitor cells and their microenvironment.

Another novel tool that would aid in the development of bioactive therapies for disc degeneration is artificial intelligence (AI). AI is a tool that has the potential to improve the prevention, diagnosis, and treatment of diseases.83 One study developed an AI-based tool to predict the risk of developing disc degeneration.84 Data on individual patients’ demographics, risk factors, and occupation were collected and fed into several algorithms to train this tool. Overall, this tool can be used by physicians to monitor a patient’s risk of developing disc disease. Similarly, AI has been used extensively to screen for naturally occurring therapeutic compounds that inhibit IVD degeneration.85 This has led to the development of tumor necrosis factor alpha inhibitors, tyrosine kinase inhibitors, and IL-1β inhibitors for halting the progression of disc disease. As such, the continued adoption of AI in the development of bioactive therapies for degenerative disc disease may further our understanding of key molecular targets to enhance tissue repair.

Altogether, innovations in bioactive therapies for degenerative disc disease underscore the importance of including cells, biomaterials, and soluble factors to enhance long-term healing and promote tissue regeneration.

ACKNOWLEDGMENTS

The authors would like to acknowledge the contributions of Thom Graves, who created the spine illustration on the right side of Figure 1. The authors would also like to acknowledge the contributions of Anne Stanford, who provided professional editing services.

Abbreviations and Acronyms

AF

Annulus fibrosus

AI

Artificial intelligence

CRISPR

Clustered regularly interspaced short palindromic repeats

ECM

Extracellular matrix

DAPS

Disc-like angle-ply structures

HDC

High-density collagen

IL

Interleukin

IVD

Intervertebral disc

MSC

Mesenchymal stem cell

MSC-Exo

Mesenchymal stem cell–derived exosome

NP

Nucleus pulposus

PLGA

Poly(lactic-co-glycolic acid)

TARP

Tension-activated nanofiber patch

TE-IVD

Tissue-engineered intervertebral disc

TGF-β

Transforming growth factor beta

Footnotes

Conflict of interest statement: R. Härtl reports consulting for DePuy Synthes, Brainlab, and Aclarion and financial relationships with RealSpine and OnPoint. This work was supported by the National Institute of Health (grant numbers 5TL1TR002386–08, NIH 3T32AR078751–03S1, and 5TL1TR0002386–07).

CRediT AUTHORSHIP CONTRIBUTION STATEMENT

Alikhan B. Fidai: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft, Writing – review & editing. Ashley Cardenas: Conceptualization, Writing – original draft, Writing – review & editing. Chibuikem A. Ikwuegbuenyi: Conceptualization, Writing – original draft, Writing – review & editing. Anthony Robayo: Conceptualization, Writing – original draft, Writing – review & editing. Noah Willett: Conceptualization, Writing – original draft, Writing – review & editing. Ibrahim Hussain: Conceptualization, Project administration, Supervision, Writing – original draft, Writing – review & editing. Roger Härtl: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. Lawrence J. Bonassar: Conceptualization, Data curation, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing.

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