Introduction

Spine disorders represent a significant burden to the general population. Moreover, the prevalence of degenerative conditions increases with age and affected population may suffer from long-term disability [1]. Conditions affecting spine mainly include symptomatic degenerative disc disease (DDD), spinal stenosis, radiculopathy, facet joint arthropathy, and sacroiliac joint pain. Symptoms arising from these conditions can be chronic axial back pain, neuropathic pain, or neurologic symptoms such as loss of motor and/or sensory functions. All of these symptoms may have a tremendous impact on mobility and quality of life. Other spinal pathologies such as spondylolisthesis or scoliosis may develop due to biomechanical changes secondary to the disc disease [2]. The most severe conditions affecting spine include spinal cord injuries (SCI), caused by trauma or by nontraumatic causes such fracture, stenosis, cancer, spondylosis with myelopathy, central cord syndrome, subluxation, or disc herniation [3].

Management of this heterogeneous group of conditions is either conservative or surgical. Conservative management of degenerative conditions includes physical therapy (therapeutic exercises, modalities for pain control), pain medications, or muscle relaxants. As a next step or as an addition to previously mentioned modalities, interventional pain management such as steroid injections, neural ablations, and neuromodulation may be needed [4, 5]. In patients with degenerative spinal conditions, surgical procedures are oftentimes necessary and may be minimally invasive such as micro-discectomy or may require more extensive operation including laminectomy or intervertebral fusion [6]. While supported by evidence for short-term pain and functional improvement, all currently used modalities lack long-term benefits. Furthermore, invasive treatments are associated with acceleration of the degenerative process, or side effects subsequent to altered biomechanical integrity [7]. Therefore, novel treatment modalities are under investigation, and the field of regenerative medicine is on the rise.

The term rehabilitation describes a process of recovery of the organ’s original functions. The field of regenerative medicine is integrating into regenerative rehabilitation, and biologic-based modalities represent a rapidly developing group of treatments fitting into this category [8•]. Safety and efficacy of biologics have been investigated in several musculoskeletal conditions such as osteoarthritis, cartilage lesions, fractures, tendinopathies (e.g., Achilles tendinopathy, plantar fasciitis, epicondylosis), and spinal conditions [9•]. Biologics including platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), extracellular vesicles (EVs), gene therapy, or growth factors represent the latest experimental treatments for the aforementioned conditions [9•]. Research effort aims in this area are reduction of pain, faster recovery, and prevention of the disease progression. Based on the preclinical science studies, it has been hypothesized that those goals may be reached via biologic-based modalities through their immunomodulatory and trophic effects. Reduction in anti-inflammatory cytokines and enrichment in growth factors may help with injury healing and reconstituting missing tissue [10•, 11•, 12].

This review will summarize the current evidence for treatment of the most common spine conditions encountered in rehabilitation medicine applying biologics and specifically will discuss painful facet arthropathy and DDD.

Degenerative Disc Disease

Intervertebral disc degeneration is a widely prevalent condition although commonly asymptomatic in many people. The degenerative process is aggravated with aging, but other significant factors play a role in its pathophysiology, including weight, smoking history, genetic predispositions, or nutrient environment within the disc [13]. Interestingly, genetic predisposition is most probably determined by polymorphisms in metalloproteinase and aggrecan genes [14]. Some of the mechanisms behind degenerative process have been described in detail; however, others are still not well understood. A balance between anti-degenerative and pro-degenerative factors leading either to injury or healing remains to seem fragile and is still being explored [13, 15,16,17,18].

The latest treatments for DDD focus on shifting the pro-degenerative environment to more neutral or pro- healing environment with the use of various types of biologics such as platelet-rich plasma, gene therapy, stem cells, or growth factors [19•]. The next generation biologics are being developed using tissue engineering technology. These treatments may be delivered via intradiscal and subchondral intraosseous injections.

Platelet-Rich Plasma

A systematic review of animal studies on the use of PRP for disc degeneration demonstrated that PRP may have positive impact on disc height, MRI T2 intensity, and histological grade [20]. Recently, it has been shown that PRP may induce increase in collagen II and aggrecan production and decrease of matrix metalloproteinase-1 (MMP-1) in porcine intervertebral disc cells treated with tumor necrosis factor (TNF)–alpha [21]. Meta-analysis of five papers published between 2016 and 2018, including one randomized controlled trial (RCT) and assessing PRP in degenerative disc disease, revealed improvements in pain scores at 6 and 12 months [11•, 22,23,24,25,26]. A double-blinded RCT treated 47 patients with either PRP or contrast agent (control). The PRP group had significant improvements in terms of pain, function, and patient satisfaction compared with the control group during follow-up at 8 weeks [25].

One of these preliminary prospective studies using intradiscal PRP shows promising results within 6-month follow-up in terms of pain relief. Up to 47% of subjects had at least 50% improvement in visual analog scale (VAS) and 30% in Oswestry disability index (ODI). However, this study possessed a major limitation in terms of lacking discogram procedure to determine the source of pain [22].

Cell Therapies

Stem cells are thought to have trophic functions and mitigate the inflammatory process [27]. They have been shown to improve pain symptoms and function in preliminary studies of musculoskeletal conditions such as in osteoarthritis [28•, 29]. In the past years, cell transplantation has been receiving increased popularity. Many types of cells have been used in the treatment of DDD ranging from intervertebral disc (IVD)–derived cells, chondrocyte-like cells, MSCs, induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESs) [30]. Also, it is important to note that some of these cells may be used in several forms, e.g., such as minimally manipulated (first generation, G1), culture-expanded (second generation, G2), preconditioned (third generation, G3), or further modified by genetic modifications (fourth generation, G4). The fifth generations (G5) are iPSCs. (Fig. 1). This framework is helping to understand how extensively the stem cells have to be processed before use [31]. Recently, IVD progenitor cells have been studied and are to be considered in the disc regeneration therapies in the future [32].

Fig. 1
figure 1

Represents a framework for five different generations of mesenchymal stem cells depending on the level of post-isolation processing. First generation of stem cells (G1) are minimally manipulated, second generation (G2) are culture-expanded, third generation (G3) are lineage-directed or pre-conditioned, fourth generation (G4) are genetically modified, and fifth generation are iPSCs. Reprinted by permission from Springer Nature Customer Service Centre GmbH: (Springer Nature, Springer eBook, Scientific Basis for Stem Cell Therapy, Luke A. Law, Christine L. Hunt, Wenchun Qu, 2019)

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Five human studies were published in the past 3 years compared with two studies total in the previous years. This increase is despite mixed evidence from animal studies and despite several possible limitations potentially affecting efficacy. Some of the problems include unknown survival of transplanted cells in the harsh disc environment or cell ability to improve this environment after the transplantation. More questions arise on the real impact on improving patients’ symptoms and on the effective and reliable evaluation of improvements [15]. It is important to mention that some risks related to intradiscal procedures have been found. In the rabbit studies, leakage of the cells into the epidural space and subsequent formation of osteophytes have been described [33]. Therefore, it is necessary to exercise caution during human studies and inject stem cells into contained discs only.

A meta-analysis including one RCT and six lower-level evidence studies evaluates the effects of various types of cell treatments on disc degeneration [11•]. These therapies were using bone marrow–derived stem cells (BMSCs), allogeneic juvenile chondrocytes, and activated nucleus pulposus cells. One safety and feasibility study evaluated the long-term safety of hypoxia pre-conditioned BMSCs when assessing patients 6 years after the study completion. There were no adverse events and patients’ symptoms generally improved [34]. Another single-arm study applying autologous MSCs in hyaluronic acid noticed significantly improved VAS, ODI, and the 36-Item Short Form Health Survey (SF-36) scores in 60% of patients at 1-year follow-up. Interestingly, three patients had increased disc water content [35]. Discograms were used to confirm painful discs, which is not always a standard in disc studies. An RCT demonstrated pain relief, improved function, and Pfirrmann scores after allogeneic BMSCs were injected into discs compared to the control. However, one of the limitations was that the control consisted injections to the paravertebral musculature and not to the discs [36].

Currently, there are about four completed studies available for DDD employing MSCs on clinicaltrials.gov and other three studies are pending recruitment start. The largest stem cell phase III study is expecting results in 2021 and is evaluating the effectiveness of allogeneic mesenchymal precursor stem cells in DDD. Bone marrow–derived subpopulation was selected from the MSCs using monoclonal antibodies. The primary endpoints are relief in pain at least by 50% measured by VAS score and at least 15 points in ODI. The previous phase of this trial showed that it was safe and effective in 100 patients with chronic low back pain due to DDD [20]. The dose of six million cells demonstrated superiority over the use of hyaluronic acid and saline only in terms of function and pain, and the effects persisted for at least 3 years. The results were superior to the dose of 12 million cells [37•].

Recently, a short report on ongoing phase I/II trial enrolling 24 patients with symptomatic lumbar disc herniation described transplantation of hydrogel with autologous chondrocytes. No adverse events were reported at 1 year [38].

Gene Therapies

Gene therapy for disc regeneration has been explored in recent years. Discs are immunologically isolated, and therefore, gene therapies with antigenic vectors can be realistically considered to ensure long-term expression of therapeutic proteins [39•]. In 1999, adenovirus-associated transfer of transforming growth factor (TGF)–beta was successfully performed in rabbit degenerative disc model [40] and many other studies using adenovirus-associated virus (AAV) followed [41,42,43,44]. However, when deciding between viral and non-viral vectors, the non-viral vectors are considered a better choice because they lack risks related to infections or tumorigenicity [19•, 45].

Beyond classical expression of recombinant proteins in viral gene therapy vectors, the latest trends are the utilization of other molecular vectors for gene delivery including liposomes, DNA-ligand complexes, or gene gun techniques. Furthermore, RNA-therapeutics holds promise for enhancement of disc repair based on the ability of regulatory RNA molecules including siRNAs, miRNAs, and lcn RNAs to modify gene expression in a sustained fashion. Because such RNAs are versatile tools, they have gained rapidly in popularity [19•].

In addition, extracellular vesicles derived from stem cells or other mesenchymal cell types have considerable promise for disc repair or regeneration [46, 47]. Of particular note is that EVs can hold a diverse cargo of molecules including proteins, mRNAs, and miRNAs. A considerable strength of EVs is that while they are cell-derived, they represent cell-free agents with therapeutic potential. Another advantage is that while EVs can be naturally derived from mesenchymal stem cells and other sources, they may also be possible to program EVs by molecular engineering approaches that permit overexpression of proteins, mRNAs, or miRNAs in the parent cells that produce EVs. Beyond the experimental hurdles that still need to be taken to develop reliable EV-based approaches is that regulatory hurdles may emerge when considering whether a cell or EV-based bio reagent is still considered a drug or otherwise a minimally manipulated biological agent. Nevertheless, the EV field is moving rapidly and it is likely that effective strategies for improving DDD will emerge.

Facet Joint Arthropathy

Facet joints connecting the vertebrae are synovial joints that, similar to knee joints, can undergo osteoarthritic changes. Facet joint degeneration is associated with cartilage loss, subchondral response, and hypertrophy [48] and often coexists with disc degeneration and spondylolisthesis [49]. Various biologics have been studied showing evidence of pain relief and function improvement in osteoarthritis of other joints [50,51,52,53,54]. However, when we searched the use of these treatments in human studies for painful facet joint arthropathies, remarkably, we found that three studies have been reported very recently.

Platelet-Rich Plasma

Platelet-rich plasma is hypothesized to have effects in healing through growth factors, cytokines, and morphogens released from the platelets [55]. These represent the decellularized first responders during tissue injury and blood vessel rupture. To date, three clinical studies used platelet-rich plasma as a biologic to mitigate joint degeneration. First study has shown that injection of PRP into facet joints in 19 patients resulted in statistically significant improvement in The Roland-Morris Disability Questionnaire (RMQ) scores and 10% improvements in ODI [56•]. One study compared PRP with corticosteroids. Both PRP and steroid treatment had pain and functional benefits in terms of VAS, ODI, and RMQ scores, but the benefits of PRP persisted longer and even increased over time [57•]. Interestingly, one retrospective pilot study involving 86 patients with low back pain injected each patient with a total of three injections of PRGF (plasma rich in growth factors) in the patients’ back. One dose was a facet joint injection; one dose an epidural injection; and one dose an intradiscal injection. This treatment showed gradually decreasing VAS scores with a decrease by 90% at 6 months [26].

Other Modalities

There has been no report on the safety and efficacy of MSC therapy for facet joint arthropathy. To explore the safety of MSC injection in facet joints, the US FDA has recently approved phase I clinical trial using adipose-derived MSC for the treatment of painful lumbar facet arthropathy [58]. It is hypothesized that MSC injection into the facet joints will not pose significant risks to the patients. This is extrapolated from the facts that MSCs have demonstrated a safety profile in many published studies for the treatment of knee osteoarthritis [28•, 29, 53] and in spine conditions including intradiscal injections and intrathecal injections [59,60,61]. Although only lower-level evidence studies using MSC treatments are currently available for the treatment of knee osteoarthritis according to the recent meta-analyses [28•, 53, 62, 63], some randomized controlled trials showed preliminary efficacy in terms of pain relief and improved function. In addition, there are about 12 active and 16 completed clinical trials published on clinicaltrials.gov that may bring stronger evidence in the near future.

Gene therapy aiming at anti-inflammatory effects by the introduction of interleukin-1 receptor antagonist (IL-1Ra) molecule using AAV vector has shown promises in the treatment of synovial joint osteoarthritis. The first gene therapy in the USA for the degenerative joint disease have been cleared by the FDA for the phase I clinical trial and is reportedly recruiting patients according to clinicaltrials.gov [64, 65••, 66.

If successful, this may provide a direction for the gene therapy for degenerative spine conditions.

Conclusions

Spinal conditions represent a diverse group of musculoskeletal and neurological diseases that are often refractory and require long-term treatment for pain and function. Regenerative medicine therapies may offer hope and healing with a new paradigm of treatment. For degenerative conditions, mesenchymal stem cells have demonstrated reasonably good feasibility and safety profiles, while their short-term efficacy and long-term benefit remain to be carefully established by further randomized clinical trials. The current progress in regenerative medicine to translate research findings into clinical trials provides encouragement that biologics may emerge as new clinical service lines for spinal conditions.