PRP and Stem cells Injection : Its applications in discopathy Congrès conjoint AQMSE-ACMSE meeting 2017 Dr André Roy Chef service de physiatrie du CHUM Clinique de physiatrie et de médecine du sport de Montréal Clinique Regen MD
Disclosures Partner of Regen MD, an orthopedic regenerative medicine clinic
Objectives At the end of this presentation, the attendee will: Understand challenges facing intradiscal regenerative therapies Know the litterature on intra-discal mesenchymal stem cell therapy Know the litterature on intra-discal PRP therapy
Introduction The standard of care for treating disc degeneration involves conservative non-surgical or surgical treatment that target symptomatic relief and musculoskeletal stabilization. Currently, there is no therapy targeting the reversal of disc degeneration The use of regenerative therapies for treating disc herniation or degeneration is a new and attractive therapeutic option However it remains is a challenge
Challenges of intra-discal regenerative tx Hostile environment for any kind of cells Avascular-hypoxic structure-biggest avascular structure of the body Nutrients only indirectly accessible through diffusion Acidic, not suitable for cells survival Poor inherent healing potential Disc made of 2 totally different structures: Nucleus pulposus, amourphous hydrophilic proteoglycan-rich gel Annulus fibrosus, fibrocartilage tissue consisting of a lamellated collagenous rings
MSC are smart cells Depending on micro-environment that they are exposed to MSC will exhibit different phenotype and have multiple functions: Regenerative action (angiogenic, mitogenic, anti-apoptotic, antiscarring Immunomodulatory action (other cells are called to help in the healing process) Anti-inflammatory action. MSC are smart cells that adapt their function to the environment
Human studies Few human studies in the litterature Phase 1 and 2 trials Results are promising Additional therapeutic options for patients Targeting the reversal of disc degeneration Experimental tx
Human studies Health Canada and FDA only authorize therapies that are minimally manipulated, eg centrifugated MSC cannot be enzymatically activated MSC cannot be cultivated-expanded Unless it is done under an IRB study Its clinical application is limited
Human studies Indications for intra-discal regenerative therapies: Chronic LBP DDD or DDD and small herniated disc (<5mm) Refractory to all conservative treatments Not indicated for: Large herniated disc Spinal or foraminal stenosis
Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up Pettine K et al, International Orthopaedics (SICOT) (2016) 40:135 140 Prospective,open-label, non-randomised, two arm study 26 patients with moderate to severe discogenic LBP as defined according to the following criteria: Centralized chronic LBP that increased with activity For at least six months Unresponsive to nonoperative management for three months
Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up Pettine K et al, International Orthopaedics (SICOT) (2016) 40:135 140 Abnormal disc morphology on MRI A modified Pfirrmann score of 4 7 (0-8) A Modic grade II change or less Disc height loss of <30 % compared to an adjacent normal disc Baseline Oswestry Disability Index (ODI) score of at least 30 on a 100- point scale Baseline LBP of at least 40 on a 100-mm VAS
Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up Pettine K et al, International Orthopaedics (SICOT) (2016) 40:135 140 Of the 26 patients, seven required discography to confirm affected disc levels All other patients were injected based on MRI. Bone marrow was aspirated (BMA) from the iliac crest(80 90mL) The BMA was centrifugated to produce a bone marrow concentrate (BMAC)
Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up Pettine K et al, International Orthopaedics (SICOT) (2016) 40:135 140 Approximately 2 3 cc of BMAC was injected per symptomatic disc Total of 5400 to 8100 MSC (CFU-F) per disc Clinical evolution was followed using ODI, VAS tests at 3, 6, 12 and 24 months Baseline and 12-month MRI were analysed by a blinded, independent radiologist
Results No complications reported from the BMA or disc injection. 92 % (24/26) avoided surgery through 12 months, while 81 % (21/26) avoided surgery through two years.
Results The average ODI and VAS scores were significantly reduced rapidly at 3 months and sustained 24months (p 0.001)
Results 20 patients had follow-up MRI at 12 months: Eight patients (40%)improved by one Pfirrman grade, while the remaining twelve patients maintained their previous score None of the discs worsened.
In conclusion: This study provides evidence of safety and feasibility of autologous bone marrow MSC injection for discogenic pain Pain relief and functional improvement observed 2 years following a single injection. 8 of 20 patients had signs of disc regeneration Round 1 to the smart cells!
Intervertebral Disc Repair by Autologous Mesenchymal Bone Marrow Cells: A Pilot Study Orozco L, Soler R et al, Transplantation 2011;92: 822 828 10 patients DDD and persistent LBP that did not respond to conservative treatment X 6 months Discogenic pain was confirmed by provocative discography in all patients Bone marrow was harvested from the iliac crest(80 90mL) MSC were expanded for 21 to 28 days
Intervertebral Disc Repair by Autologous Mesenchymal Bone Marrow Cells: A Pilot Study Orozco L, Soler R et al, Transplantation 2011;92: 822 828 20 +/-5 M MSC were injected in the NP of the affected disc Clinical evolution was followed at 3, 6 and 12 months with evaluation of LBP VAS, ODI and SF-36 MRI at baseline, 6 and 12 months were done to assess the disc height and water content
Results Both VAS and ODI scores were quickly and statistically reduced at 3 months, followed by a more modest additional improvement at 6 and 12months At all time, scores were statistically significant The improvement in sciatic pain was significant at 6 and 12 months as compared to baseline The improvement in pain and ODI at 12 months demonstrated a strong positive correlation with the values at 3 months (r=0.79;p<0.0001)
Results Pain and disability improvement as a result of MSC treatment Level of improvement is plotted as a function of the initial pain score value or disability index Results for the relief of lumbar pain, sciatic pain and ODI are all included The continuous line has a slope of 1 and represent the perfect treatment The dotted line represent the MSC tx group and has a slope of 0.71, indicating that the analgesic effect of treatment with MSC approached a 71% efficacy, which is excellent
Results SF-36 showed a significant improvement of the physical component (P<0.05) but no change in the mental The improvement in pain was accompanied by a parallel improvement in disability and SF-36 results
Imaging The disc height didn t change significantly Water content of the treated disc that did not change at 6 months had a statistically significant increase to 0.72+/-0.03 at 12 months
In conclusion: LBP and function were significantly improved through 12 months by a single injection Decrease in pain was rapid and sustained The analgesic effect of treatment with MSC approached a 71% efficacy. Disc water content was increased at 12 months Round 2 to the smart cells!
Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial Noriega DC et al, Transplantation Publish Ahead of Print DOI:10.1097/TP.0000000000001484 Randomized controlled study 24 patients with chronic LBP Unresponsive to conventional treatments for at least 6 months DDD Pfirrmann grade II-IV Randomized in 2 groups Experimental group (n=12): 25M MSC in 2 ml of saline per disc Control group (n=12): Sham infiltration of paravertebral musculature close to the affected disc(s) with 2 ml of 1% mepivacaine
Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial Noriega DC et al, Transplantation Publish Ahead of Print DOI:10.1097/TP.0000000000001484 Bone marrow was harvested from the posterior iliac crest of 5 healthy donors and expanded for 27 ± 2 days Clinical evolution was followed using ODI, VAS tests and SF-12 at 8 days, 3, 6, 12 months Quantitative MRI was performed at baseline, 6 and 12 months
Results Both VAS and ODI medians were significantly reduced in favour of the MSC group at 3 months and the difference was maintained at 6 and 12 months In the sham group, a fast decrease of pain was observed at the 8 th day but there was no further improvement thereafter
Results The perfect treatment has a slope of 1 The efficacy of the tx is equal to the slope of the line The MSC group dotted line has a slope of 0.28 ± 0.07 significantly different from 0 (p<0.001) The sham group dotted line has a slope of 0.15 ± 0.10, not significantly different from 0 (p=0.13)
Results Physical and the mental component scores of the SF-12 did not show significant difference between the 2 groups
Imaging Evolution of Pfirrmann staging was clearly different in the control and in the experimental groups at 12 months. In the MSC-treated group there was a statistically significant improvement of Pfirrmann stage (3.68 ± 0.13 to 3.18 ± 0.17 (p<0.01)) In control group, there was a statistically significant deterioration of Pfirrmann stage (3.15 ± 0.15 to stage 3.78 ± 0.16 (p<0.001))
Imaging The height of the affected discs decreased by 0.38 ± 0.19 mm in the sham group and by only 0.04 ± 0.19 mm in the MSC group In the MSC group, the height of adjacent healthy discs decreased by 0.07±0.10 mm as compared to 0.04 ± 0.19 mm in the cell-treated discs In the cell-treated discs the image density increased by 22 ± 11 %, compared to only 6 ± 8 % in controls Howeve, in all cases the differences were not statistically significant
In conclusion Intra-discal allogeneic MSC injection is safe Improvement in pain and disability in the MSC group was observed through 12 months Many imaging parameters were improved by MSC injections Disc degeneration was reversed or stopped by MSC Round 3 to smart cells!
Lumbar Intradiskal Platelet-Rich Plasma (PRP) Injections: A Prospective, Double-Blind, Randomized Controlled Study Yetsa A et al, PM R. 2016 Jan;8(1):1-10 Prospective, double-blind, randomized, controlled study 47 patients with chronic LBP Unresponsive to conventional treatments for at least 6 months Discogenic pain confirmed by provocative discography followed by CT scan Presence of grade 3 or 4 annular tear Small herniated disc < 5mm Randomized in 2 groups
Results Experimental group (n=29): Provocative discography was followed by 1-2 cc of PRP at one or multiple level No data about platelets and other cell count injected Control group (n=18): Provocative discography was followed by 1-2cc of contrast medium Functional Rating Index (FRI), Numeric Rating Scale (NRS),SF 36 - questionnaires, Modified North American Spine Society (NASS) Outcome Questionnaire were collected at 1 week, 4 weeks, 8 weeks, 6 months, and 12 months
Results At 8 weeks, all patients who had no clinical improvement were unblinded. If they were initially in the control group, they were offered intradiscal PRP 15/18 patients crossed over to the treatment group Those in the PRP group who had no clinical improvement were managed with other conservative treatments or surgery.
Results At 8 weeks: PRP group demonstrated significant improvement vs control group in: FRI score (P =.03) NRS best pain (P =.02) Patients who received PRP were more likely to report satisfaction with their treatment (NASS patient satisfaction index) 56% of the participants were satisfied with their treatment compared with 18% of control participants.
Results At 8 weeks: There was no statistical difference in the self-reported current pain, worst pain, SF-36 Pain and Function scores (P =.16, P =.09, P =.08, and P =.44 respectively) PRP and control group outcomes were not compared after 8 weeks
Results At 6 months (n=28): Significant improvement as compared to baseline in: FRI (P <.01) NRS Worst Pain (P <.01), SF-36 Pain (P =.03)
Results At 12 months (n=21): Significant improvement in: FRI (P <.01) NRS Worst Pain (P <.01), SF-36 Pain and physical functioning scores (P <.01)
Results No complication reported
In conclusion Intra-discal injection PRP is safe Rapid decrease in pain and disability was observed at 8 weeks and maintained at 6 and 12 months No MRI follow-up to see if morphologic disc changes occurred with clinical improvement
Take home messages Intra-discal MSC and PRP injections are safe and not associated with serious adverse effects in humans. MSC not only improve pain and function but has the potential to stop or reverse disc degeneration Many more clinical trials with better methodology are necessary but the current study are very promising