Biologics

Intro: Biologics

This category refers to the Holy Grail of spine medicine. Scientific studies are ongoing for the development of medical compounds that actually “heal” disc degeneration/injury. While the problem remains unsolved, science is creeping closer everyday.

A recent review/meta-analysis by our colleagues at the Spine Intervention Society (SIS) provided a reasonable synopsis of the state of the literature heading into 2022 (The Spine Journal 22 (2022). Systematic Review/Meta-Analysis The effectiveness of intradiscal biologic treatments for discogenic low back pain: a systematic review Schneider BJ et al). In their conclusions they wrote, “When appropriate inclusion criteria were applied, some observational data suggests that intradiscal biologic agents may be effective treatments for discogenic LBP. When aggregation of data was possible, 22/42 (52.4%, 95% CI: 37%−67%) study participants achieved >50% relief of LBP following intradiscal injection of PRP with a minimum follow-up of six months. For MSC therapies, depending on how loss-to-follow-up is counted, success rates of >50%improvement in LBP at six months were 23/43 (53.5%, 95% CI: 38.6%−68.4%) (as reported) or 23/59 (39.0%, 95% CI: 26.5-51.4%) (worst-case analysis) at six months. According to GRADE the published evidence supporting the use of intradiscal MSCs and PRP is of very low quality. Given the poorly regulated and rapidly expanding US direct-to-consumer stem cell industry, high quality explanatory trials are needed to better assess the true effectiveness of these treatments.”

These words of caution are to be respected. That being said, the early data suggests there is a sub-section of patients for whom this type of intervention can be quite effective. Select patients will have a encouraging prognosis for responding and therefore a favorable benefit:risk profile

Fibrin Sealant (Fibrin sealant information is for history and education only)

At the 17th Annual Scientific Meeting of the International Spine Intervention Society (ISIS) an abstract entitled “Intradiscal injection of fibrin sealant for the treatment of symptomatic lumbar internal disc disruption: results of a prospective multicenter IDE pilot study with 6-month follow-up” was presented by authors Way Yin, MD et al. The purpose of this study was to assess the safety and preliminary efficacy of BIOSTAT BIOLOGX® Fibrin Sealant in human adults with chronic symptomatic lumbar internal disc disruption (IDD). The sealant occludes the anular fissures and lays down a tissue repair matrix. Essentially, it functions as a physical barrier between inflammatory substances in the disc and nerves within the fissures, and serves as a scaffold for tissue repair.

The original study included 15 adults with chronic axial low back pain (CLBP). These patients had “failed” conservative therapy and were deemed appropriate for this study after provocation. Initial data suggested intradiscal fibrin sealant injection might improve pain and function in selected patients with IDDS.

In 2014, results from a multi-centre randomized controlled trial (RCT) demonstrated the efficacy of this fibrin sealant compared with placebo. Clinically significant improvements in pain and function were demonstrated at 24 months follow up. Tremendous excitement was generated from this study.

Unfortunately, the Phase III trial for fibrin sealant did not meet expectations.  This larger multi-centre RCT was stopped after 6 months due to the fact early results were disappointing. Fibrin sealant did not demonstrate a satisfactory level of efficacy versus placebo and has not become the standard of care.

Stem Cell Therapy

Stem cell use has become the object of media frenzy, stoking, both public and research interests, due to the potential for tissue regeneration. Autologous (from our own body) stem cell use requires the harvest of large numbers of cells with subsequent use of special laboratory techniques for clonal expansion (multiply) to a differentiated (specialized) nuclear chondrocyte cells (the cells that regenerate our disc material). Next, these specialized cells need to be careful placed into your own disc in a way that is safe and effective.

A controlled clinical trial of this technique, using stem cells is in process. The use of mesenchymal stem cells (MSC) has been studied in animals with some early investigations of MSC implantation in humans. Large quantities of MSC can be obtained from peripheral blood, bone marrow, or fatty tissues using commercially available liposuction techniques. In all cases, the retrieved biologic material can be processed quickly in the operating room to yield a cellular product that can be injected intradiscally. It appears that some clinics around the world may be offering this modality, although human clinical trial data are unavailable to evaluate this practice.

The media has driven a lot of attention toward the use of stem cells to treat many medical conditions. Back pain is no exception. We are optimistic stem cell therapy will be proven successful. However, we should wait for the scientific data before making conclusions. Currently, this type of intervention is not available in Canada. As stated above, patients need to be selected quite carefully to ensure a favorable benefit:risk ratio. Dr. Helper can assist in evaluation of an individual’s candidacy and a referral to a colleague in the U.S. (if appropriate).

Intradiscal PRP (Platelet Rich Plasma)

The scientific literature regarding the use of platelet-rich plasma (PRP) injections for the treatment of spine pain conditions is in its infantile stage.  There are limited studies assessing the efficacy of PRP for the treatment of discogenic low back pain (degenerated disc or disc injury), facet joint pain (otherwise known as zygapophyseal joint pain or z-joint pain), or sacroiliac joint pain (intra-articular joint pain or pain emanating from the supportive ligaments).  While PRP is proposed to enhance the body’s natural wound healing mechanisms, it is not apparent from human studies that the tissue objectively “regenerates”.  In other words, if one were to complete an MRI of an individual’s spine prior to PRP treatment, followed by an MRI a year later, it is unlikely that clear evidence of degeneration reversal will be evident.  Rather, the changes are more subtle, occurring at a cellular level. 

In the spine, just like the other joints of the body, there is a delicate balance between degeneration processes and regeneration processes.  As we get older, degeneration tends to outweigh regeneration and we begin to degrade (we develop osteoarthritis).  The function of regenerative cells (e.g. fibroblasts and chondrocytes) start to lose their battle with degenerative enzymes (e.g. metalloproteinases).  Similarly, growth factors that promote healing, such as TGF-beta, IGF-1, and BMP-2, are produced in insufficient quantity to counteract cytokines, such as interleukin-1, TNF-alpha, and others.  By boosting the body’s natural heat-healing mechanisms, this delicate balance is gently pushed back in the other direction, slowing the degenerative process.  How this helps with “pain” is not completely understood. 

Although there is incomplete knowledge of how PRP helps spine pain conditions, there is a trend in the early literature for benefit.  It appears as though a good percentage of patients will benefit.  The benefits tend to be incomplete (partial relief), but significant.  The benefits tend to kick in at around one month post-injection.  The benefits maximize at three months pos-tinjection.  The benefit tends to last from three months through 6 and 12 months, in early studies.   

Discogenic Low Back Pain:  Six early studies in the treatment of discogenic low back pain are worth review:

1. Akeda K, et al. Intradiscal injection of autologous platelet-rich Plasma releasate to treat discogenic low back pain: A preliminary clinical trial. Asian Spine J 2017;11(3):380-389.
2. Levi D, Horn S, Tyszko S, et al. Intradiscal platelet-rich plasma injection for chronic discogenic low back pain: preliminary results from a prospective trial. Pain Med. 2016;17(6):1010–1022.
3. Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, et al. Lumbar intradiskal platelet-rich plasma (PrP) injections: a prospective, double-blind, randomized controlled study. PMR. 2016;8(1):1–10.   
4. Navani A, Hames A. Platelet-rich plasma injections for lumbar discogenic pain: a preliminary assessment of structural and functional changes. Tech Reg Anesth Pain Manag. 2015;19(1-2):38–44.
5. Schepers MO et al. Effectiveness of intradiscal platelet rich plasma for discogenic low back pain without Modic changes: A randomized controlled trial. Interventional Pain Medicine 1 (2022)
6. Lutz C, et al. Clinical outcomes following intradiscal injections of higher-concentration platelet-rich plasma in patients with chronic lumbar discogenic pain. Int Orthop 2022 Jun;46(6):1381-1385

Akeda et al. treated 14 patients with WBC poor PRP.  Patients were followed for one year.  Pain intensity improved by greater than 50% at one month with results sustained at one year.  Similarly, significant functional improvements were demonstrated at one month, but were more impressive at six months and 12 months.  Followup MRI did not show objective evidence of “regeneration”.

Levy et al. published a prospective trial of 22 patients who were treated with WBC rich PRP.  All patients followed up at two months.  Nineteen out of 22 patients followed up at six months.  Greater than 50% pain relief was reported in 32% of patients at two months and 47% of patients at six months.

Tuakli-Wosornu et al. completed a prospective double-blind randomized control study.  After recruitment, 18 patients were analyzed in the control group and 29 patients were analyzed in the treatment group.  Treatment results were modest.  Although statistically significant improvements were shown in pain and function, the improvements were small.  For example, there was a greater than 2-point improvement in pain on the numeric rating scale (pain from 1-10) for pain.  However, the functional data showed only borderline results.

Schepers et al. completed a prospective, randomized controlled study. Participants were randomized to receive 1.0 cc intradiscal PRP (intervention) or 1.0 cc Saline with 0.2g Kefzol (control with antibiotic). Data on pain, physical function, and the participants’ general perceived health were collected at 1 week, 4 weeks, 2 months, 6 months, 9 months and 1 year.Of the initial 98 (49 intervention, 49 control) patients randomized, 89 (91%) (44 intervention, 45 control) with complete outcome data were analyzed. Groups were balanced at baseline. Their data showed that participants who received intradiscal PRP showed no significant improvement in pain or functionality compared to the control group at 1 year follow up.

Lutz et al. assessed clinical outcomes following intradiscal injections of higher-concentration (> 10 ×) platelet-rich plasma (PRP) in patients with chronic lumbar discogenic pain (37 patients) and compared outcomes with a historical cohort (29 patients). This retrospective study showed that pain and function scores significantly improved following intradiscal injections of > 10 × PRP (p < 0.001). These improvements were greater than those reported by the historical cohort (p = 0.004 and 0.016, respectively). Additionally, the satisfaction rate was higher in patients receiving > 10 × PRP compared to those receiving < 5 × PRP (81% vs. 55%). Findings from this study suggested that clinical outcomes can be optimized by using PRP preparations that contain a higher concentration of platelets.