Low back pain is one of the most debilitating conditions worldwide, associated with substantial socioeconomic and healthcare implications [1], and is strongly associated with degenerative disk disease (DDD) [2, 3]. Providing effective treatment for DDD has proven to be difficult. Current therapies range from conservative treatments, which include medications, physical therapy, physical modalities, and injections, to more invasive surgical options, which include disk arthroplasty, spinal fusion, and disk decompression [4, 5]; however, these current therapies rarely stop the progression of degeneration and do not restore the native functional state of the disk, focusing instead on management of symptoms and not their etiology [6].

A novel approach to the treatment of DDD utilizes regenerative therapies with the aim of both treating and reversing degeneration, as well as enhancing current treatment modalities. Regenerative therapies, including stem cell therapy, biologic growth factors, and gene therapy, have demonstrated promising results in reversing the degenerative process [7]. In this chapter, we will discuss their role in DDD, peripheral joint disease, and musculoskeletal injuries.

Stem cell injection into disks aims at repairing lost cells and matrix, while increasing proteoglycan (PG) content responsible for the disk’s organization [8]. These injections have also demonstrated to have both anti-inflammatory and immunosuppressive properties [9, 10]. Mesenchymal stromal cells (MSCs) are one available source for this cell-based repair [11–13]. MSCs are a heterogeneous population of multipotent cells that are capable of differentiating into chondrogenic, osteogenic, and adipogenic lineages but are not associated with hematopoietic cell lines. Sources for these MSCs include the bone marrow (BM-SC), synovial membrane, and adipose tissues [14–17].

The most common source of MSCs is from the bone marrow and is often harvested at the posterior iliac crest, which has a high MSC density and provides similar culture expansion potential compared to other tissue sources [18–20]. MSCs are obtained either from the patient themselves (autologous transplantation) or from other donors (allogenic transplantation). The MSCs are harvested, concentrated, and in some cases, induced and differentiated with the help of growth factors. Disk cells can also be harvested to seed the scaffolding that will assist the MSC in regenerating the affected disk.

With the patient lying prone, local anesthetic is administered at the injection site. A 22-gauge needle is placed via fluoroscopy in the standard posterior lateral discogram approach with two-needle technique [21]. Approximately 2–3 mL of stem cells is then injected into the symptomatic disk. Patients may require a short-term pain medication regimen following the procedure as well as use of a back brace; restricted physical activity is recommended.

A common indication for stem cell use in DDD is moderate-to-severe discogenic low back pain, which is unresponsive to other nonoperative management, with the goal of avoidance or delay of progression to lumbar fusion or disk replacement [21]. Additional criteria for inclusion into previous investigations include Pfirrmann scores (score of 4–7), Modic grade changes on MRI, disk height loss compared to nonpathologic disks, Oswestry Disability Index (ODI), and Visual Analog Score (VAS).

General exclusion criteria include an abnormal neurologic exam, symptomatic compressive pathology due to stenosis or herniation, and significant spondylolysis or spondylolisthesis [21]. Some postulate that a Thompson score of 4–5 would be a contraindication for stem cell therapy, because the extreme microenvironment would impair successful stem cell regeneration. Additionally, grade V annular tears, with full thickness radial tears and leakage of contrast on discography, may be considered a contraindication for cellular injections.

There have been encouraging results from several clinical trials. A 2011 study investigating injection of autologous bone marrow MSCs (BM-MSCs) into the nucleus pulposus (NP) of affected disks revealed 90% improvement in pain relief and water content of the injected disk [11, 14]. A subsequent study injecting autologous stem cells into symptomatic degenerative disks in surgical candidates demonstrated statistically significant improvement of ODI and VAS at all follow-up time points, sustained pain relief, and overall improvement in modified Pfirrmann scores [21]. A retrospective study demonstrated that 67% of patients got pain relief from stem cell injection at 5–12 months, and 42% continued to have relief at 13–24 months [22]. The safety profile of bone marrow concentrate injections in 101 patients with various bone healing abnormalities was also investigated. No complications were discovered including new bone formation, injections, tumor induction, or morbidity related to extraction on the iliac crest [22, 23].

The use of stem cell therapy also extends into treating numerous musculoskeletal diseases and injuries. Stem cells have been used to aid in healing and functional restoration of bone regeneration in patients with impaired restoration [24]. Treatment of tibial nonunion with osteoprogenitor cells was found to stimulate osteogenesis in 18 of 20 patients [25]. Osteonecrosis is also thought to respond to cell-based therapies [24]. Additionally, stem cells have also demonstrated substantial utility in cartilage pathology. Autologous chondrocyte implantation has become an established treatment for focal articular cartilage defects larger than 4 cm², or as a secondary treatment following failure of initial treatments such as microfracture [26]. This technique has yielded good to very good long-term clinical results in the majority of patients [27, 28].

Intra-articular injections of MSC have been successfully used to treat osteoarthritis (OA). Initial pilot studies evaluating injection of BM-SC into patients with knee OA have demonstrated safety and feasibility of the procedure, and MRIs of injected knees 2 years later have demonstrated increased cartilage and meniscal thickness [29–31]. VAS and functional outcomes in 50 knee OA patients were significantly improved with MSC injection compared to arthroscopic debridement only [32]. MSCs were also found to improve physical therapy assessments [33] and have demonstrated efficacy in the prevention of posttraumatic arthritis [34]. A systematic review of a total of 844 procedures of local autologous MSC injections for OA revealed that the procedure was safe, with no reported major adverse effects of MSC implantation [35]. Another study evaluating 227 clinical cases of intra-articular MSC injection for OA reported three self-limiting cell-related complications as the only safety issues [31]. No malignant transformations were seen at two-year follow-up.

Furthermore, stem cells have been combined with surgical debridement of talar dome defects and found to improve function after 2 years [36]. Core decompression with local delivery of bone marrow auto grafts improved Harris Hip scores and significantly reduced the need for arthroplasty when performed prior to collapse of the joint surface [37].

Epicondylitis has also been a target of regenerative therapies. One study of 20 patients with ultrasound-confirmed, refractory medial epicondylitis received autologous blood injection to the site of maximum injury [38]. Eighty-five percent of patients reported statistically significant reduction in VAS and Nirschl pain score at both 4 weeks and 10 months without complications. A study of 35 patients with ultrasound-confirmed refractory lateral epicondylitis also demonstrated significant reductions in Nirschl and VAS scores [39]. Autologous dermal fibroblasts were also found to be safe and effective in treating both lateral epicondylitis and refractory patellar tendinopathy [40].

With the advancement of molecular technology, production of recombinant proteins, including growth factors (GFs), has increased to an industrial scale. Disk degeneration results from dyssynergy between anabolic and catabolic regulators. A central strategy to delay progression of DDD is to utilize GFs to strengthen disk integrity by shifting metabolic status from catabolic to anabolic. This is accomplished by stimulating cells in the disk with appropriate GFs to upregulate matrix metabolism [41]. In vitro investigations suggest that disks themselves are capable of expressing and producing numerous GFs. Thompson et al. first described the anabolic effects of growth factors including TGF-β, epidermal growth factor, and basic fibroblast growth factor on PG synthesis [42]. Others have demonstrated that IGF-1 stimulated PG synthesis in a dose-dependent manner [43] and that recombinant human bone morphogenetic proteins (BMP) like BMP-2 increased cell proliferation and mRNA expression of collagen in disk cells [44]. Other BMPs like BMP-7, also known as osteogenic protein-1 (OP-1), was found to strongly upregulate the production and formation of PG and collagen [45]. OP-1 was further found to enhance nucleus and annular repair [46] and cause PG and collagen synthesis in both early and advanced stages of DDD; however, synthesis was more effective early in degeneration [45, 47].

The successful induction of matrix synthesis has paved the way for clinical applications of GFs, especially in spinal fusion surgery. Spinal fusion depends largely upon bone grafting [48], and because of the morbidity associated with the gold standard of bone augmentation, autologous iliac crest bone graft (ICBG) , bone graft substitutes were sought. Given BMPs successful osteoinductive properties, recombinant human BMP-2 has been used as an autologous bone graft substitute in single-level lumbar interbody fusion from L4-S1 with a proprietary cage [48, 49]. Clinical outcomes as well as fusion rates were comparable to ICBG [50, 51]. Though the risk of any adverse events was high, they were similar between the two groups [50, 51].

OP-1 was also approved for use after it demonstrated safety and efficacy both as an adjunct to ICBG for noninstrumented posterolateral fusions in patients with degenerative spondylolisthesis, and as an alternative to ICBG [52–54]. Numerous studies also support OP-1 as a safe and effective treatment of fractures and atrophic nonunions [52, 55, 56].

Another novel, minimally invasive regenerative strategy using GFs involves intradiscal injection of a fibrin sealant. Fibrin sealant has been developed to address physical findings associated with symptomatic internal disk disruption by sealing annular nociceptors from inflammatory compounds [57]. Additionally, fibrin’s persistent presence may also promote cellular repair of annular fissures. One specific formulation of fibrin, known as BIOSTAT BIOLOGIX , significantly downregulated inflammatory cytokine synthesis and proteolytic enzymes [58, 59]. It also upregulated anabolic cytokines and maintained nuclear volume while mitigating negative mechanical consequences of surgical denucleation [57].

The Biostat® System is one system combining an intradiscal delivery of BIOSTAT BIOLOGIX fibrin sealant along with active ingredients including human fibrinogen, thrombin, calcium chloride, and synthetic aprotinin acetate [57, 59]. In a pilot study of 15 patients, 87% demonstrated at least a 30% reduction in low back VAS compared to baseline at 26-week end-point [56]; however, success criteria for primary analysis of the Biostat® System were not met in a subsequent Phase III study [60]. Additional clinical trials are necessary to confirm its efficacy.

Gene therapies may provide additional treatment options, especially at the most advanced stage of degeneration. In genetic therapy, new genes are inserted into diseased cells or tissues using viral vectors or naked deoxyribonucleic acid [61]. Nishida et al. demonstrated the feasibility of direct in vivo transduction of disk cells with an adenoviral vector [61, 62]. Zhang et al. successfully stimulated PG and collagen production by transducing adenovirus vectors carrying various BMP genes [63]. The delivery of gene combinations has also been investigated, as TGF-β, BMP-2, and IGF-1 were found to synergistically increase PG synthesis in vitro [64].