Abstract
Spine surgery technology and technique have improved considerably over the past few decades, thereby widening the breadth of pathologies that may benefit from surgical intervention. However, entities such as non-radicular low back pain, degenerative disc disease, and chronic spinal cord injury have limited if any reliable surgical treatment. As the body of literature and the reliability of preparation strategies for orthobiologics such as platelet-rich plasma and mesenchymal stem cells continues to improve, so has their potential for use in the treatment of spine pathology. The number of clinical studies and high-level trials that evaluated the use of orthobiologics in fields such as degenerative disc disease/discogenic back pain, post-decompressive pain, spinal cord injuries and surgical adjuncts during discectomy or fusion procedures has grown significantly over the past decade. While this field remains immature and most works are either uncontrolled or evaluate a small number of patients, the body of evidence that supports the efficacy of orthobiologics in areas where traditional surgical intervention is less effective continues to increase. Here, we review the current body of literature that assesses the use of orthobiologics in spine surgery and provide additional discussion as to current questions and future directions for the field. Particular attention will be paid to high-quality trials that have been completed or are currently in progress, and comment as to the quality and shortcomings of current protocols will be made.
Keywords
Introduction
Chronic lower back pain affects more than 1 in 3 adults, and 1 in 10 have degenerative disc disease. The combined all-cause medical costs of these two conditions over 3 months in 2019 were over $800 billion USD. 1 Musculoskeletal disease has been repeatedly identified as the most common cause of high health service utilization in multiple countries, 2 and the demand for care due to musculoskeletal pain in some regions has increased 2- to 4-fold over a 40-year period. 3 As the global lifespan and the prevalence of obesity increase and elderly patients remain active for longer, the cost burden from chronic pain and degenerative disease is expected to increase.
There has been a significant increase in the demand for services related to lower back and neck pain over the past 20 years, particularly among elderly (age 65 and older) patients. Dieleman et al 4 reported a 6.5% year-over-year increase in spending on back and neck pain from 1996 to 2013, costs mostly driven by demand for pharmaceuticals, inpatient care, and visits to the emergency department. Such cost trends suggest that novel pharmaceuticals that provide lasting pain relief and keep patients out of the hospital can be both patient and cost-effective.
Regenerative medicine is defined by the United States Food and Drug Administration (FDA) as the translation of biology and engineering into therapeutic approaches for the regeneration, replacement or repair of organs. 5 Nearly all exogenous and endogenous compounds that can be procedurally manipulated or dosed to achieve a clinical effect can be defined as orthobiologics. Targets and techniques of particular interest have focused on optimizing the healing environment, inducing and accelerating the inflammatory and regenerative cascade, and directly replacing damaged cells.
Popular applications of such “orthobiologics” include the treatment of osteoarthritis, tendinopathy, and cartilage repair. Initial supporters of orthobiologics touted their potential to improve and reverse the underlying causes of the patient’s pain and dysfunction. However, much of the basis for these therapies was in vitro. Early clinical reports that studied the benefits of orthobiologics used “proprietary,” poorly described synthesis techniques on small samples of selected patients. High-quality works were rare. 6 As such, the literature inconsistently supported the efficacy of orthobiologics, insurance rarely reimbursed for such therapies, and patient adoption was consequently slow.
The emergence of recent high-quality evidence has prompted reconsideration of the value of orthobiologics and regenerative medicine in the treatment of pain and degenerative disease, particularly of the spine. Areas of particular interest include generalized back and neck pain, degenerative disk disease, post-decompression neuroinflammation, spinal cord injuries, and adjuncts to spinal fusions. This review aims to introduce and define common terms in orthobiologics and regenerative medicine, and to review the current evidence on the clinical efficacy of prolotherapy, platelet-rich plasma (PRP) and mesenchymal stem cell (MSC), therapy via intradiscal, facet joint, epidural or sacroiliac joint delivery.
Types of Orthobiologics
Prolotherapy
Prolotherapy introduces a noxious substance into an area of damaged or diseased tissue to induce an inflammatory and healing response. Prolotherapy in orthopedics has two desired effects: (1) trigger the inflammatory cascade to promote inflammatory cell influx and the subsequent deposition of collagen as a healing reaction and (2) “temporary neurolysis” of peripheral pain receptors for symptomatic relief. Used since at least the 1930s, many substances have been used as irritants for prolotherapy, including phenol, chemotactic agents, and glycerin. 7 More recent works have used hyperosmolar dextrose to dehydrate local cells to death, triggering a focal inflammatory and healing reaction. 8 Bae et al 9 in their meta-analysis of 10 studies and 750 patients who had their chronic musculoskeletal pain treated with prolotherapy found that targeted hypertonic saline injections were superior to normal saline and exercise for chronic pain due to any musculoskeletal etiology. However, the extent of this analysis was limited by the heterogeneity of the conditions studied and the lack of long-term follow-up beyond 1 year.
Platelet-Rich Plasma
PRP is an ultra-concentrated dose of the patient’s platelets. The dense granules, o-granules and lysosomes inside of platelets contain growth factors and cytokines that modulate inflammation, angiogenesis, chemotaxis and cellular proliferation. 10 PRP’s exact mechanism of action is unclear, but there is some evidence that its effects are anatomy- and disease-dependent. 11 In contrast with cellular delivery protocols, PRP is entirely a milieu-inducing therapy. 12 PRP contains few if any viable cells and instead accelerates the host’s own endogenous processes to produce a therapeutic effect. 13 Noback et al 14 in their cross-sectional survey study reported that PRP is the most common exogenous therapy used by sports physicians in the treatment of muscle and tendinous injuries both surgically and non-surgically, in particular rotator cuff tears, tennis elbow, patellar tendinopathy and articular cartilage injuries. A recent work documenting current practices in orthopedic regenerative medicine found that PRP was significantly less costly for patients than other commonly used treatments such as bone marrow concentrate and bone marrow aspirate concentrate. 15
Mesenchymal Stem Cells (MSCs)
Stem cells are capable of self-renewal and can differentiate into multiple phenotypes. Stem cells can be adult or embryo-derived, with the latter capable of a broader range of differentiation. However, given the ethical and legal boundaries and concerns regarding the use of embryonic stem cells, translational research has largely focused on adult stem cells. The multipotent nature of adult stem cells permits their differentiation into cell types of a similar origin. Such cells are capable of being harvested from the host and readministered into target injured tissues.
The large majority of orthobiologic stem cell therapies utilize adult mesenchymal stem cells. The minimum criteria for a cell to be considered an MSC per The International Society for Cellular Therapy 16 are: (1) the cells must be plastic adherent in culture; (2) the cells must express the surface antigens (CD105, CD73, and CD90) expressed by all MSCs, and not the surface antigens expressed by differentiated cells such as leukocytes, monocytes/macrophages, and endothelial cells; and (3) the cells must be capable of differentiating into osteoblasts, chondroblasts, and adipocytes. Bone-marrow aspirate concentrate (BMAC) is a non-processed aspirate typically of the iliac crest that is considered stem cell rich. MSCs are isolated and sorted following harvest from various tissues and include bone marrow-derived MSCs (bmMCs), adipose-derived MSCs (aMSCs) from subcutaneous fat through liposuction or lipoaspiration, synovial-derived MSCs (snMSCs) from the synovial and joint tissues, and birth-tissue-derived MSCs (btMSC) from the amnion, placenta and umbilical cord.
Two newer forms of MSC therapy include cellular bone matrices (CBM) and demineralized bone matrices (DBM). CBM utilizes allogeneic mesenchymal stem cells to combine osteogenic, osteoinductive, and osteoconductive factors into one product.17,18 A prospective study found that 95.3% of patients undergoing lumbar surgery receiving an adjunctive allograft CBM achieved successful fusion at 24 months with significant improvements in Oswestry Disability Index (ODI), Visual Analog Scale for back pain (VAS-Back), and Visual Analog Scale for neck pain (VAS-Neck). 17 While this study was limited in that it assessed collective data on several different surgical approaches rather than assessing individual procedure effectiveness, this shows a promising role of CBM in regenerative orthopedics. DBM are also formed from allograft that undergo processing to remove the protein matrix of the bone. A review that analyzed current trials on spinal fusion showed limited support for the use of DBM alone and rather suggested its use as a graft extender. 18
Clinical Applications of Orthobiologics in Spine Care
Discogenic Pain and Degenerative Disc Disease
Pain originating from the axial anatomy is common, with an annual point prevalence of 13% for low back pain and 4.9% for neck pain.19,20 While the origin of 85% of chronic lower back pain is unidentifiable, 21 up to 50% of the low back pain treated in specialized pain or orthopedic clinics is discogenic, while another 33% is facet-related. 22 Degenerative disc changes including desiccation and annular tearing can be used to identify potential pain drivers, and techniques such as computed tomography (CT) discography can reproduce symptoms and confirm disc integrity to avoid leakage. 23 While the current body of literature supports the clinical efficacy of orthobiologics in the treatment of discogenic and non-radiating low back pain, the level I evidence supporting these indications is for PRP and MSC intradiscal injections for discogenic pain, PRP injections for facet disease, epidural injections of autologous conditioned serum and prolotherapy, and prolotherapy for sacroiliac joint pain. An additional study on facet joint prolotherapy reported negative results, and at the time of this work no intervention had more than one supporting level I study.
The large body of literature that utilizes prolotherapy in the axial anatomy is in the treatment of discogenic disease. Miller et al 24 performed an uncontrolled prospective study in which 76 patients with lower back pain, radicular symptoms and intact disc anatomy received up to 5 biweekly disc space prolotherapy injections of a 50% dextrose, 0.25% bupivacaine solution. Sustained improvement in pain scores of 71% were reported by 43.4% of patients 18 months after treatment. Bupivacaine was used to provide rapid pain relief and confirm treatment localization, and Ohtori et al 25 found no evidence that bupivacaine accelerated disc degeneration in a 5-year comparison of discoblock (bupivacaine alone) and discography (saline). Derby et al 26 explored the benefits of the addition of 0.5% chondroitin sulfate and 20% glucosamine hydrochloride to 50% hypertonic dextrose prolotherapy in a group of 35 patients with lower back pain refractory to prior conservative and surgical treatments. Significantly decreased pain as measured with visual analogue pain score (VAS) after 18 months was noted in 65.6% of patients, although 81% of participants reported at least one post-procedure pain flare-up.
Initial pre-clinical studies evaluating the effects of PRP on human disc cells demonstrated decreased apoptosis, improved proteoglycan synthesis, and reduced expression of inflammatory cytokines.27-29 Levi et al 30 in their prospective cohort study reported that 47% (9/19) of patients with refractory lower back pain with imaging or discographic localization reported at least a 50% decrease in pain and 30% improved function as measured with the Oswestry Disability Index (ODI) 6 months after a single PRP treatment. Tuakli-Wosomu et al 31 in their randomized double-blind controlled trial of 47 patients with >6 months of refractory low back pain at one or more levels localized with discography, no surgical history, and mild to moderate disc degeneration defined as a protrusion <5 mm on magnetic resonance imaging (MRI) and a grade 3 or 4 annular fissure on discography were treated with either PRP or contrast alone. PRP was delivered at a single dose to one level or divided into equal doses at multiple levels. While follow-up was only 8 weeks, patients who received PRP had significantly improved pain, patient satisfaction, and function compared with controls. The concentration of PRP appears to correlate with its treatment effect. Jain et al 32 positively correlated the beneficial effects of PRP 6 months after treatment with the platelet counts of the administered sample in a prospective study of 25 patients with chronic lower back pain (r = 0.7 for the ODI and r = 0.73 for the pre-procedure numerical rating scale). A meta-analysis of these three prospective trials concluded that intradiscal PRP significantly reduced VAS pain scores and improved function as measured with the ODI 6 months after treatment, although short-term benefits (improvements at time points earlier than 6 months) were mixed. 33 However, the authors noted that only one of these trials was controlled, the preparation of the PRP in all three studies was heterogeneous (one work quantifying the variability in the dosages given), and long-term effects >6 months were not available. A way to standardize PRP dosing may be to use PRP releasate, which is the concentrated growth factors and cytokines within the PRP isolated from a clotted sample. Akeda et al 34 injected PRP releasate into 14 patients with at least 3 months of refractory, localizable discogenic back pain and monitored participants for a mean of 10 months. Mean VAS pain score and Roland-Morris Disability Questionnaire were significantly improved from baseline measurements 1-6 months after treatment and persisted 1-year post-injection in the 9 patients who presented for follow-up. Zielinski et al 35 conducted a double-blind, randomized, placebo-controlled study on a small cohort of 26 patients with discogenic pain to determine the effects of PRP on clinical improvement, ultimately finding clinical improvement in 17% of patients, but also a clinical decline in 5% of the group. More recently, however, Navani et al 36 conducted a multicenter, prospective, crossover RCT with long-term follow-up of 12 months and found that PRP led to significantly lower discogenic low back pain using patient reported outcomes on the numeric rating scale. This study overcame limitations of previous work such as dosing and follow-up time. Future work should replicate this study at a larger scale and assess outcome differences by disc injury.
The initial evaluation of cellular-directed therapies in the treatment of discogenic and degenerative spine disease focused on the reimplantation of cultured autologous intervertebral disc chondrocytes (ACI). Anderson et al 37 in their review of cellular therapies in the treatment of degenerative disc disease identified cell viability, source, preparation, and dosing as key considerations when evaluating the efficacy of ACI, and while identifying some reliability of using imaging to measure improvement emphasize the importance of measurable clinical outcomes. Interim and subgroup analyses of early participants in the EuroDISC randomized controlled trial that compared discectomy + ACI vs discectomy alone found that patients treated with ACI had significantly improved pain and patient-reported function and disability scores that persisted for at least 2 years.38,39 The difference in efficacy between autologous and cell-line chondrocytes is unclear, and the advantages of commercially available chondrocyte preparations include improved regulation and dosing consistency. Couric et al 40 in their uncontrolled prospective pilot trial injected 1-2 mL of 107/mL of commercially purchased juvenile chondrocytes into 15 participants, noting a significant improvement in patient-reported outcomes 12 months after injection and radiographic improvements 6 months post-injection.
Early reports of the use of MSCs in the treatment of spine disease focused on treating degenerative disease, radiculopathy and spinal instability in patients who were poor surgical candidates. The first report of the clinical use of MSCs in degenerative disc disease by Yoshikawa et al 41 followed two patients with chronic lower back pain and lower extremity numbness who received bmMSCs impregnated into a collagen sponge and delivered via a discectomy approach into a diseased segment. Both patients reported persistent symptom relief two years after treatment, and improved water content of the target disc space was observed on the follow-up MRI. These favorable findings were replicated by the follow-up 10-patient pilot study by Orozco et al, 42 and the viability of the direct injection of btMSC into the disc with good 2-year response was shown by Pang et al. 43 Elabd et al 44 reported a more than 50% improvement in the strength and mobility of 3/5 patients 4-6 years after treatment with hypoxic cultured bmMSCs. The viability of aMSCs in degenerative disc disease was demonstrated by Kumar et al, 45 who noted a marked improvement in VAS, ODI, and Short Form-36 (SF-36) scores that lasted for 12 months in 6 of the 10 patients who “responded” to MSC therapy. Six-year safety and radiographic efficacy of bmMSCs was demonstrated by Centeno et al. 46
The efficacy of stem cell therapies appears to be dose and source dependent. The dose dependency of BMAC intradiscal injections was demonstrated by Pettine et al, 47 who in a trial of 26 patients showed that BMAC improved symptoms at high and low concentrations, but a higher concentration of cells was necessary for functional improvement at all ages, and for pain improvement in patients > 40 years of age. A 3-year post-operative follow-up of these patients reported that only 6 (23.1%) went on to require surgical intervention for their degenerative disease, while the functional and VAS pain improvements persisted in the other 20.48,49 The importance of delineating between responders and non-responders is best seen in the randomized controlled trial by Noriega et al, 50 who randomized 24 patients between 25 million allogeneic MSCs injected into the disc or paraspinal infiltration of bupivacaine (n = 12 per group). The authors note that the pain and functional outcomes of the experimental group split clearly into a group of responders (n = 5) and non-responders (n = 7). The responders mirrored near-perfect therapeutic outcomes while the non-responders matched the control group almost perfectly. A mean 3.5-year follow-up study of these same patients showed that responders remain as such long term, while only a small number (3/7) of non-responders converted to responders. 51 Likewise, a randomized clinical trial by Gornet et al 52 evaluated the efficacy of allogeneic disc progenitor cell intradiscal injections in a cohort of 60 patients with single-level lumbar degenerative disease, separating this group into low and high-dose administrations. Ultimately, the high-dose group achieved the primary endpoint of mean visual analog scale pain improvement greater than 30% at 52 weeks (−62.8%, P = 0.005) which was maintained until week 104. On the other hand, the low-dose group showed minimal improvements, thereby exhibiting the dose-dependent nature of this intervention. Cannon et al 53 conducted a pre-clinical study that showed MSC effectiveness in intervertebral disc degeneration is tissue source dependent. They found that amniotic membrane-derived MSCs were the most effective with the lowest rates of senescence and apoptosis under acidic microenvironments.
Delivery medium may be key to a higher rate of treatment response. PRP and aMSCs delivered as stromal vascular fraction after mini-lipoaspirate into one or more degenerative discs were well tolerated (no severe adverse effects) and significantly improved flexion, VAS pain ratings and quality of life scores as measured with the Short Form-12 (SF-12) and the Short Form McGill Pain Questionnaire 6 months after treatment. 54 There may also be a role for structural rather than substantive augmentation of the degenerative disc. The Viable Allograft Supplemented Disc Regeneration in the Treatment of Patients with Low Back Pain With or Without Disc Herniation (VAST) prospective randomized multicenter trial randomized 220 subjects at 15 clinical sites to percutaneous fluoroscopy-guided injection of commercial viable allograft vs saline into a diseased intervertebral disc space, reporting that allograft-treated patients had improved ODI and VAS scores 6 and 12 months post-injection (VAS pre-op 54.8, 6 months 16.0, 12 months 12.3; ODI pre-op 53.7, 6 months 18.5, 12 months 15.7) vs controls (VAS pre-op 55.3, 6 months 41.0, 12 months 19.7; P-values not provided). 55
Post-Decompression Pain
Surgical decompression is indicated in the setting of radicular pain caused by a structural abnormality, such as a disc herniation following the failure of an attempted course of non-surgical management. However, pain can persist after decompression. This post-operative radiculitis is defined as transient radicular pain after initial symptoms and resolving within 6 months of surgery. 56 Boakye et al 57 reported in a cross-sectional analysis of laminectomy patients that 77% of those surveyed had clinically significant short- or long-term “post-decompressive neuropathy,” which the authors defined as the development of unrelated neuropathic pain following a lumbar laminectomy for chronic degenerative disease. While that work was limited to central decompressions, this phenomenon appears to exist after peripheral nerve decompressions as well. Multiple reports have linked post-decompressive neuropathic pain with a response similar to that of an ischemic-reperfusion injury, which is manifest by monocyte infiltration into the dorsal root ganglia and peripheral nerves, microglia and astrocyte activation and the increased expression of acute phase cytokines such as TNF-α, IL-1β, and IL-6, which in turn mimics and triggers a neuro-inflammatory response.58-61
The large body of data on the characterization and treatment of post decompression pain is pre-clinical. Musolino et al 62 injected bmMSCs into the 4th lumbar dorsal root ganglia of rats who underwent single ligature nerve constriction of their sciatic nerve. Animals treated with bmMSCs had a reduced number of allodynic responses to cold stimuli, but treatments did not resolve either mechanical or thermal hypersensitivity 56 days after treatment. However, central treatment via intrathecal injection of bmMSCs by Chen et al 63 in a similar sciatic nerve constriction model observed both long term (4-5 weeks) relief of neuropathic pain and evidence of migration to the affected dorsal root ganglia via CXCL12-mediated chemotaxis. The authors speculated that the relative efficacy of their intrathecal injection model vs more direct delivery mechanisms may be due to the local trauma caused by the injection. MSCs may also have a role in the treatment of more mechanical forms of chronic pain. Guo et al 64 performed a long-term (22-week) observational study of intravenous vs local delivery of bmSCs following experimental ligation of the tendon of the anterior superficial part of the rat masseter muscle, which is a known cause of chronic orofacial pain in this model. Both delivery methods resulted in lasting, long-term pain relief via central and peripheral nerve receptor downregulation.
A single high-level study evaluated the use of orthobiologics in the mediation of post-decompressive symptoms. A randomized controlled trial of 269 patients evaluated the use of amniotic-derived products (ADP)—which have been found to reduce the expression of MMP- and TGF-β-mediated scarring and contraction in vitro 65 —and BMAC at the surgery site following endoscopic lumbar decompression. 66 Patients received either ADP, BMAC, both, or no supplementation. The authors reported that patients treated with ADP or BMAC had significantly improved VAS leg pain and back scores over 9 months of follow-up, although this translated into modest, short-lived improvements in function (ODI improvement only 2 weeks post-op) and SF-36 (up to 4 = month improvement) compared with untreated patients. No synergy between ADP and BMAC was observed.
Spinal Cord Injury
Spinal cord injuries (SCI) represent financial and personal devastation for the patient and a substantial loss of quality-adjusted life years. Occurring in approximately 180000 people per year, 67 mortality from SCIs is twice as likely in developed countries, 68 and outcomes suffer in regions with poor infrastructure and immature early resuscitation and rapid airway management strategies during initial management and stabilization. 69
Early management of SCIs largely focuses on reducing inflammation, minimizing ischemia, and stabilizing/decompressing critical vertebral injuries. 69 Minimizing inflammation while maintaining spinal cord perfusion is prognostic of neurologic recovery. 70 However, while evidence supporting suppressing the inflammatory response with intravenous steroids during the acute injury period is controversial at best, 71 pre-clinical works support the potential use of MSCs to halt and potentially reverse the Wallerian degeneration and scarring that lead to permanent neurologic injury. Yousefifard et al 72 injected 1 million bmMSCs or btMSCs into the injury site of a rat SCI model. Both MSC groups improved motor recovery and neuropathic pain relief, and btMSCs had superior post-injection survival compared with bmMSCs. Additional pre-clinical works utilizing MSCs reported improved locomotor function, decreased glial scarring, 73 reduced autophagy at the injury site, 74 and improved local angiogenesis75,76 and myelination. 77 These benefits have largely been rendered through reduced inflammatory and degradative markers such as matrix metalloproteinases and hypoxia inducible factor, 78 and increased anabolic factors such as transforming growth factor-beta. The Notch pathway may also play a role in neurologic recovery after severe spinal cord compression. Cheng et al 79 reported increased levels of vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and Notch-1 1 week after decompression of the injured spine, and that Notch-1 inhibition inhibited post-decompression motor recovery. Questions regarding the utility of pre-clinical therapies relate to localization, survival and vector-attributable functional improvement. The final of these questions is hardest to answer, and largely relies on the creation of a reliable “steady-state” SCI, which is easiest to achieve in a chronic injury model. Ryu et al 80 in a retrieval analysis of aMSCs transplanted into a canine subacute (1 week) SCI model noted increased neural differentiation of the stem cells in the setting of quantitative improvements in nerve conduction velocity and Olby pelvic limb functional scores. Localization was key to efficacy, and therapeutic efficacy can be enhanced with a viable scaffold that maximizes therapeutic localization and duration. The meta-analysis by Yousefifard et al 72 of pre-clinical works evaluating scaffolds and MSCs in the treatment of acute SCIs found that the combination of scaffolds with either btMSCs or bmMSCs improved motor function recovery compared to the use of a scaffold (standardized mean difference 2.00, P < 0.0001) or vector alone (standardized mean difference 1.58, P < 0.0001). Phase II testing of commercially produced MSC-impregnated scaffolds is ongoing (NCT02688049). Moreover, Mu et al 81 observed the effects of human umbilical cord mesenchymal stem cells (hUCMSCs), neural stem cells (NSCs), and epidural electrical stimulation (EES) on enhancing recovery in murine spinal cord injury models. In vitro, NSCs showcased pathways associated with increased differentiation and expression of growth factors and in vivo, combined cell therapy along with EES were shown to decrease inflammation and enhance neuron repair more efficaciously than either intervention alone. This pre-clinical study further provides evidence for the utilization of orthobiologics in the treatment of spinal cord injury in combination with other methodologies such as neuromodulation.
While pre-clinical studies are largely optimistic regarding the efficacy of MSCs on acute SCI outcomes, current clinical evidence is limited primarily due to our inability to predict how acute injury patients will recover with supportive interventions alone. Geffner et al 82 reported that bmMSC delivery via direct spinal cord, spinal canal, or intravenous injection into patients with an acute SCI was safe, without systemic or oncologic side effects. Xiao et al 83 presented two-patients, one with a complete T11 SCI and another with a complete C4 injury, into whom they placed a commercially produced umbilical btMSC graft during the decompressive surgery. The authors reported that both patients improved markedly over a 1-year follow-up, although could not identify the MSC scaffolds as the reason why. A phase I/II clinical trial (NCT02917291) is currently enrolling patients with acute SCI for treatment with allogeneic aBMC, and another seeks patients for bmMSC therapy (NCT04528550).
Glial scarring represents a physical block to axonal regeneration in the setting of a chronic SCI. Scar resection has been discussed, but the efficacy of this strategy is predicated on optimizing the microenvironment for axonal healing and providing a scaffold to direct neurons across the resected scar. 84 The safety of MSC transplantation via intravenous or local site delivery has been established in small phase I clinical trials.30,85-91 Cristante et al 92 reinfused autologous cryopreserved bmMSCs into 39 randomly selected patients with a complete cervical or thoracic SCI at least 2 years after injury. The authors reported that 26/39 patients (66.7%) had an objective increase in lower extremity somatosensory evoked potentials 9 months after stem cell treatment, although no factors predictive of treatment response were identified. A phase III trial of a single intradural MSC administration in patients with a chronic SCI (minimal 12 months post-injury) was terminated due to poor efficacy (2/16 patients with motor improvement), which was attributable to the lack of multiple MSC administrations. 93 Park et al 94 had somewhat better outcomes with three separate administrations of autologous bmMSCs 4 weeks apart into patients with ASIA A or B cervical SCIs at least 1 month after injury. The authors reported that 6 months after treatment 6/10 (60%) patients had significant improvements in upper extremity motor function while 3/10 (30%) had improved completion of activities of daily living as determined by a rehabilitation specialist. The largest completed trial of intrathecal MSCs was published by El-Kheir et al, 95 who reported that bmMSCs injected into patients with chronic SCIs (minimum 12 months post-injury) resulted in functional improvement (as measured with the functional rating mean score) in 23/50 (46%) of cases 18 months post-injection, with high response rates in those with thoracic SCIs and smaller cord lesions. Of note, the comparison group used in this trial was historical, and the bmMSCs were filtered to include only those that adhered to a poly-l-lysine coated dish, which represents a departure from the preparation techniques used in earlier works. While currently enrolling phase II/III clinical trials (NCT02687672, NCT03505034, NCT03521336, NCT03521323, NCT02574585, NCT04520373, NCT03225625, NCT04213131, and NCT04288934) are designed to be adequately powered to report on the efficacy of MSCs in the treatment of acute or chronic SCIs, MSCs may also have some role in the management of sequelae related to SCIs. Sarasua et al 96 reported that autologous bmMSCs injected into a closed cavity created during pressure ulcer debridement led to uncomplicated healing without additional surgeries within 21 days of surgery in 15/22 (70.4%), and 19/22 (86.4%) healed after a single repeat treatment.
Adjuncts in Spine Surgery
Few clinical works have evaluated the impact of orthobiologics on surgical outcomes, as therapies are largely considered preventative measures. Anderson et al 97 randomized 80 subjects who underwent an elective lumbar microdiscectomy to receive either amniotic stem cells or no treatment to the microdiscectomy site following the procedures. The authors found that ADM improved ODI and SF-12 scores 24 months after surgery (ODI: 6.6 ± 1.3 for ADM, 14.4 ± 3.3 controls, P = 0.02; SF-12 scores graphed but not stated), although it was underpowered to show if ADM treatment could reduce the rate of recurrent disc herniation (0/40, 0% with ADM vs 3/40, 7.5% in the control group, P > 0.05). Kim et al 98 conducted a prospective, post-market study on Vibone Viable Bone Matrix (VBM), a cellular matrix comprising osteogenic, osteoinductive, and osteoconductive factors, and its effects on clinical and radiographic outcomes in 104 cervical and lumbar spinal fusion surgeries. At 12 months, they found improvements of 51.5% in the VAS for pain, 42.6% in the Neck Disability Index, and 55.4% in the ODI, all of which were significant. All patients achieved clinically significant improvements with fusion rates of 88.1% per patient in cervical and 97.6% in lumbar patients. Per-level fusion rates were 98.5% for cervical and 100% for lumbar surgeries. However, these findings are limited in that CBM was not compared to a control group for these reported pain outcomes.
It is challenging to measure the effects of orthobiologics on spine fusions due to the low incidence of non-unions, making such works difficult to power. Blanco et al 99 embedded BMAC into tricalcium phosphate to augment a single-level spine fusion, reporting an 80% fusion rate without adverse effects. However, this work was uncontrolled, so the actual benefit of this strategy could not be quantified. Mochida et al 100 injected 1 million activated nucleus pulposus cells into a diseased disc adjacent to a level indicated for fusion, reporting that the technique itself was safe and did not appear to accelerate degeneration, but conceded that they were unable to show that the cell therapy had any ability to prevent adjacent segment disease.
Limitations and Future Directions
Key Works Studying Discogenic Pain and Degenerative Disc Disease
FRI = functional rating index; HA = hyaluronic acid; MSC = mesenchymal stem cells; NDI = Neck Disability Index; NPS = numeric pain score; NRS = numeric rating scale; ODI: Oswestry Disability Index; PRP = platelet rich plasma; SANE = single assessment numeric evaluation; VAS = visual analogue pain score.
Key Works Studying the Use of Orthobiologics in Post-decompression Pain
Key Works Studying the Use of Orthobiologics in Spinal Cord Injury
MEP = motor-evoked potential; MSC = mesenchymal stem cells; SCI = spinal cord injury; SSEP = somatosensory evoked potentials; human umbilical cord mesenchymal stem cells = hUCMSC; neural stem cell = NSC; epidural electrical stimulation = EES.
Key Works Studying the Use of Orthobiologics as Adjuncts During Spine Surgery
Despite the numerous limitations to current works, the potential of orthobiologics is undeniable. Silverman et al 103 in their value proposition for cell-based therapies for the degenerative lumbar spine remind us that lower back pain is a leading cause of missed time from work and the most common non-oncologic indication for chronic opioid therapy in the United States. Even a measured symptomatic improvement could have a substantial impact on societal and absolute cost of care and represent a significant sparing of quality-adjusted life years that would have otherwise been lost. While cost-benefit analyses of any proposed therapy, including decision curve analysis, 104 are paramount in our current age of value-based care, it is anticipated that further advancements in orthobiologics will yield improved efficacy at a cost that is markedly lower than that of surgery.
Conclusion
The use and diversity of orthobiologics continues to expand. Spine applications are generally encouraging, although there remain few high level-of-evidence studies and current works rely on small cohorts. It is anticipated that the acceptance of orthobiologics as clinical standard of care will continue to broaden as the body of literature on these techniques improves and preparation strategies become more standardized.
Footnotes
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.