Critically Acclaimed Topic

Amanda Manzione

 

Clinical & PICO Question:

A mentor of mine recommended that I become involved in research being done in her hospital regarding the use of stem cells in regeneration of tissue for musculoskeletal injuries; strains, sprains, cartilaginous injury, etc. As a busy PA student, my schedule did not permit active participation in this research, but presented a great opportunity to review the literature for my critically acclaimed topic.

 

Q: Is the use of stem cells for musculoskeletal injury proven to improve time and quality of healing, while decreasing adverse effects from alternative therapies?

 

PICO Search Elements:

P	I	C	O
Muscle strain	Stem cell injection	Placebo	Time to heal
Ligament sprain	Stem cell	NSAIDs	FROM
Musculoskeletal injury	Mesenchymal stem cells	RICE therapy	Pain control
Cartilaginous injury	Pluripotent stem cells	Surgery
	Regenerative engineering

 

 

 

Search Strategy:

 

PubMed: “stem cell musculoskeletal injury” —> 300 results; 10 years 263 results; 5 years 172 results

Cochrane Database: “stem cell musculoskeletal injury” —> 8 results

Google Scholar: “stem cell musculoskeletal injury” —> 46K results; last 10 years19k results; 2018 4K results

 

Articles Chosen

 

1. Narayanan, Ganesh, et al. “Musculoskeletal tissue regeneration: the role of the stem cells.” Regenerative Engineering and Translational Medicine 3.3 (2017): 133-165.
   https://link.springer.com/article/10.1007/s40883-017-0036-9

Abstract

Ligament, cartilage, and meniscus injuries often have poor healing due to low vascularity and low proliferative abilities of the resident cells. Drawbacks with conventional treatment methodologies have prompted interest in a new approach we term “Regenerative Engineering” to regenerate orthopaedic tissues. The work of cells is of central importance in the Regenerative Engineering paradigm. In this regard, both differentiated cells and stem cells such as bone marrow stromal cells have been studied as sources for orthopaedic tissue regeneration. In addition, other stem cells such as those derived from peripheral blood, synovium, adipose, and other extraembryonic sources have been isolated and characterized and subsequently investigated for regenerating various orthopaedic tissues. In this review, recent developments in the stem cell-mediated regeneration of ligament, cartilage, and menisci are discussed.

2. Jevons, Lauren A., Franchesca D. Houghton, and Rahul S. Tare. “Augmentation of musculoskeletal regeneration: role for pluripotent stem cells.” Regenerative medicine 13.2 (2018): 189-206.
   https://www.futuremedicine.com/doi/full/10.2217/rme-2017-0113

Abstract

The rise in the incidence of musculoskeletal diseases is attributed to an increasing ageing population. The debilitating effects of musculoskeletal diseases, coupled with a lack of effective therapies, contribute to huge financial strains on healthcare systems. The focus of regenerative medicine has shifted to pluripotent stem cells (PSCs), namely, human embryonic stem cells and human-induced PSCs, due to the limited success of adult stem cell-based interventions. PSCs constitute a valuable cell source for musculoskeletal regeneration due to their capacity for unlimited self-renewal, ability to differentiate into all cell lineages of the three germ layers and perceived immunoprivileged characteristics. This review summarizes methods for chondrogenic, osteogenic, myogenic and adipogenic differentiation of PSCs and their potential for therapeutic applications.

3. Loebel, C, and Burdick J. “Engineering stem and stromal cell therapies for musculoskeletal tissue repair.” Cell stem cell (2018).
   https://www.sciencedirect.com/science/article/pii/S1934590918300146

Abstract

Stem cells and tissue-derived stromal cells stimulate the repair of degenerated and injured tissues, motivating a growing number of cell-based interventions in the musculoskeletal field. Recent investigations have indicated that these cells are critical for their trophic and immunomodulatory role in controlling endogenous cells. This Review presents recent clinical advances where stem cells and stromal cells have been used to stimulate musculoskeletal tissue repair, including delivery strategies to improve cell viability and retention. Emerging bioengineering strategies are highlighted, particularly toward the development of biomaterials for capturing aspects of the native tissue environment, altering the healing niche, and recruiting endogenous cells.

4. Via, Alessio Giai, et al. “Making Them Commit: Strategies to Influence Phenotypic Differentiation in Mesenchymal Stem Cells.” Sports medicine and arthroscopy review 26.2 (2018): 64-69.
   https://journals.lww.com/sportsmedarthro/Abstract/2018/06000/Making_Them_Commit___Strategies_to_Influence.5.aspx

Abstract

Tendon injuries, bone defects, and cartilage defects are complex clinical conditions leading to pain and dysfunctions. Tendon, bone, and cartilage are highly specialized and organized tissues, and the self-healing may be limited by their histologic features, or impaired by the local conditions. Furthermore, the resultant tissue often shows inferior properties compared with native tissue, leading to high rates of re-ruptures and revision surgeries. A growing field of research has explored tendon, bone, and cartilage regeneration using mesenchymal stem cells (MSCs), because of their multipotency, and because they are relatively easy to harvest. Great expectations arose from the use of MSCs in regenerative medicine in the last decade, although both the potential and the drawbacks of this method remain under reflection. This is a narrative review of the literature about different strategies to differentiate MSCs into tenocytes, osteoblasts, and chondrocytes. Challenges and limitations on the use of MSCs in vivo and in clinical practice are also discussed.

5. Levi, Allan D., et al. “Clinical Outcomes from a Multi-Center Study of Human Neural Stem Cell Transplantation in Chronic Cervical Spinal Cord Injury.” Journal of neurotrauma ja (2018).
   https://www.liebertpub.com/doi/abs/10.1089/neu.2018.5843

Abstract

Human neural stem cell transplantation (HuCNS-SC) is a promising CNS tissue repair strategy in patients suffering from stable neurological deficits from chronic spinal cord injury (SCI). These immature human neural cells have been demonstrated to survive when transplanted in vivo, extend neural processes, form synaptic contacts and improve functional outcomes after experimental SCI. A Phase II single blind, randomized proof-of-concept study of the safety and efficacy of HuCNS-SC transplantation into the cervical spinal cord was undertaken in patients with chronic C5-7 tetraplegia, 4-24 months’ post-injury. In Cohort I (n=6) dose escalation from 15 M to 40 M cells was performed to determine the optimum dose. In Cohort II an additional 6 participants were transplanted at target dose (40 M) and compared to 4 non-treated controls. Within the transplant group, there were 9 AIS B and 3 AIS A participants with a median age at transplant of 28 years with an average time to transplant post injury of 1 year. Immunosuppression was continued for 6 months’ post-transplant and immunosuppressive blood levels of tacrolimus were achieved and well tolerated. At one-year post-transplantation, there was no evidence of additional spinal cord damage, new lesions, or syrinx formation on MR imaging. In summary, the incremental dose escalation design established surgical safety, tolerability, and feasibility in Cohort I. Interim analysis of Cohort I and II demonstrated a trend towards UEMS and GRASSP motor gains in the treated participants, but at a magnitude below the required clinical efficacy threshold set by the sponsor to support further development resulting in early study termination.

 

6. De Windt, T. S., Vonk, L. A., Slaper-Cortenbach, I. C. M., van den Broek, M. P. H., Nizak, R., van Rijen, M. H. P, et al. Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons. STEM CELLS, 35(1), 256–264. 2016 doi:10.1002/stem.2475

Abstract

Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first‐in‐man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage‐derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment‐related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second‐look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline‐like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient‐own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell‐induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found.

 

7. Akgun, I., Unlu, M. C., Erdal, O. A., Ogut, T., Erturk, M., Ovali, E, et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Archives of Orthopaedic and Trauma Surgery, 2014: 135(2), 251–263. doi:10.1007/s00402-014-2136-z

Abstract

Background

Cell-based strategies that combine in vitro- expanded autologous chondrocytes with matrix scaffolds are currently preferred for full-thickness cartilage lesions of the knee ≥2 cm². Although this approach is reasonable, continuing advances in the field of cartilage repair will further expand the options available to improve outcomes.

Hypothesis/purpose

In the present clinical study, we compared the outcomes of matrix-induced autologous mesenchymal stem cell implantation (m-AMI) with matrix-induced autologous chondrocyte implantation (m-ACI) for the treatment of isolated chondral defects of the knee.

Study design

Prospective, single-site, randomized, single-blind pilot study.

Methods

Fourteen patients with isolated full-thickness chondral lesions of the knee >2 cm² were randomized into two treatment groups: m-AMI and m-ACI. Outcomes were assessed pre-operatively and 3, 6, 12 and 24 months post-operatively.

Results

Clinical evaluations revealed that improvement from pre-operation to 24 months post-operation occurred in both groups (p < 0.05). At all follow-up intervals, m-AMI demonstrated significantly better functional outcomes (motion deficit and straight leg raise strength) than did m-ACI (p < 0.05). At all follow-up intervals, m-AMI demonstrated significantly better subjective sub-scale scores for pain, symptoms, activities of daily living and sport and recreation of the knee injury and osteoarthritis outcome score (KOOS) than did m-ACI (p < 0.05). Additionally, m-AMI demonstrated significantly better (p < 0.05) scores than m-ACI for the quality of life sub-scale of the KOOS and visual analog scale (VAS) severity at the 6-month follow-up. The Tegner activity score and VAS frequency were not significantly different between the two groups. Graft failure was not observed on magnetic resonance imaging at the 24-month follow-up. m-AMI and m-ACI demonstrated very good-to-excellent and good-to-very good infill, respectively, with no adverse effects from the implant, regardless of the treatment.

Conclusion

For the treatment of isolated full-thickness chondral lesion of the knee, m-AMI can be used effectively and may potentially accelerate recovery. A larger patient cohort and follow-up supported by histological analyses are necessary to determine long-term outcomes.

 

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Narayanan, Ganesh, et al. (2017)	Literature Review	330 articles reviewed	Ligament, Cartilage, and Meniscus Regeneration.	The main advantage of utilizing stem cell-based approaches has been their versatility to undergo tissue-specific differentiation. They conclude that there is a promising future for regenerative engineering in the treatment of orthopedic injuries .	Funding from the Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, NIH R01AR063698, and NIH DP1 AR068147. Does not specify outcomes such as time to heal and pain management.
Jevons et al. (2018)	Literature Review	129 articles reviewed	Socioeconomic factors affecting care, methods for chondrogenic, osteogenic, myogenic, and adipogenic differentiation of PSCs for therapeutic applications	– The ability of PSCs to self-renew and differentiate into any somatic cell type may well prove to be a highly effective tool in the treatment of such diseases   -Treatment approaches in the future are likely to focus on tissue engineering as this would enable the existence of a quality control system, whereby 3D explants that are generated can be assessed in terms of their morphological, mechanical and physiological properties prior to implantation	Does not specify study designs Unclear outcomes specified Funding to RS Tare and FD Houghton from the Rosetrees Trust, the Faculty of Medicine and the Institute for Life Sciences, University of Southampton for PhD Studentship support to LA Jevons. FD Houghton also acknowledges funding from the Medical Research Council (G0701153
Loebel, C, and Burdick J. (2018)	Literature Review	118 studies reviewed	Limitations of current therapeutic interventions, stem cell sources and delivery strategy, biomaterials to enhance retention, strategies to enhance endogenous repair, immunomodulatory considerations	– The majority of clinical trials to date have used BM-MSCs with success in contributing to tissue repair and reduction of pain. – the establishment of MSC-based therapies in the musculoskeletal field requires evidence-based clinical trials with appropriate follow-up of clinical parameters that may also investigate the mechanism behind the therapeutic benefit. – Since cultures must be obtained under GMP conditions, cost and time to therapy are both increased.	Only looks at MSC, but from different sources. Notes limitation of cell gathering under FDA restrictions. C.L. acknowledges support from the Swiss National Foundation through an SNF Early Postdoc Mobility Fellowship, and J.A.B. acknowledges funding from the NIH (R01EB008722 and R01AR056624) and the National Science Foundation (DMR Award 1610525)
Via, Alessio Giai, et al. (2018)	Literature Review	63 articles	The effect of mesenchymal stem cells on growth factors, cytokines, as well as differentiation in the setting of tendon, bone, and cartilage healing. Differentiation strategies	– In vitro cultures show favorable results, but the results are not reproducible in vivo in animal models. The biochemical stimuli may be of too short a duration to have adequate in vivo results. – MSCs and ECM are in constant connection with each other, and local modifications of the ECM could affect the differentiation of MSC	Smallest of the literature reviews
Levi, Allan D., et al. (2018)	Cohort in 2 parts	64 enrolled, 31 passed screening: 6 in cohort I (open trial, single blind), 25 in cohort II (13 randomized to tx, 12 to control).	Tacrolimus blood levels, upper extremity motor scores, graded redefined assessment of strength, sensibility, and prehension, spasticity, pain and allodynia assessments, adverse events.	– The study revealed reliable safety and feasibility of HuCNS-SC transplantation into persons with chronic cervical SCI supported by repeated neurological, functional assessments, AE and SAE evaluations, and imaging over 12 months. – Improvements in overall UEM scores and GRASSP strength component at final follow-up were observed in those who received hand-held peri-lesional injections of human CNS-derived neural stem cells.	Small sample size, poor follow up. Unable to evaluate full impact due to premature termination of the trial. Single blind Only looks at the application in terms of spinal cord injury This work was supported by StemCells, Inc. and the respective Academic Institutions. BOCO provided funds for post-termination data collection. Dr. Allan D. Levi receives teaching honorarium from AANS and grant support from the Department of Defense. Dr. Paul Park is a consultant with Globus, Medtronic, Zimmer and Nuvasive. He receives royalties from Globus and grant support from Pfizer. Dr. Kim Anderson is a consultant for Vertex Inc. Jane Hsieh is a former consultant with Stem Cells Inc. Dr. Thomas N. Bryce receives grant support from the Craig H. Neilsen Foundation and the National Institute on Disability, Independent Living, and Rehabilitation Research.
De Windt, T. S et al. (2016)	Prospective monocenter study	10 patients, 5 of which received the standard mixture of MSCs and 5 of which received a high yield mixture (addition of 10%-20% recycled autologous chondrons for treatment of knee cartilage defects.	Primary: safety and feasibility of IMPACT (Instant MSC Product accompanying Autologous Chondron Transplantation) and demonstrate non-inferiority in adverse event rate compared to ACI (Autologous Chondrocyte Implantation). Secondary: level of clinical improvement Third: parameters of structural repair.	– rapidly isolated chondrons from debrided cartilage when combined with allogenic human bone marrow MSC is feasible and stimulates reproducible tissue regeneration and provides clinical improvement. – no treatment related adverse events observed within 1 year follow up, no inflammation detected in first 6 weeks.	Small sample size Single center study, does not imply implementation viability at other institutions Looked at application in knee cartilaginous injury. Non commercially funded by the Translational Adult Stem Cell Research Program of Zonmw which is part of the Dutch ministery of Health, Welfare, and sport.
Akgun I, et al. (2014)	Prospective, single site, single blind pilot study	14 participants, randomized 7 in m-AMI group and 7 in m-ACI group.	Evaluation before treatment and at 6, 12, and 24 mo follow up. Clinical knee examination and ROM, max strength straight leg raise, absolute strength measure, KOOS scales, Tegnar scores, visual analog scores for frequency and severity of pain, MRI analysis.	Improvement from pre-operation to 24 months post-operation occurred in both groups. At all follow-up intervals, m-AMI demonstrated significantly better functional out- comes (motion deficit and straight leg raise strength) than did m-ACI, as well as significantly better subjective sub- scale scores for pain, symptoms, activities of daily living and sport and recreation of the knee injury and osteoarthritis outcome score (KOOS). Graft failure was not observed on magnetic resonance imaging at the 24-month follow-up. m-AMI and m-ACI demonstrated very good-to-excellent and good-to-very good infill, respectively, with no adverse effects from the implant, regardless of the treatment.	Small sample size, resulting in age discrepancy between the two groups which may affect activity outcome scores. Patient bias is also possible on self-reporting subjective outcome measures. Histological outcome measures were unable to be studied, which is why MRI analyses were used. Short follow-up used for a surgical procedure that produces repair tissue that continues to develop over a 2- to 3-year period.

 

Conclusion(s):

The first study by Narayanan et al. concluded that regenerative engineering such as stem cell implantation can address some of the drawbacks of traditional surgical interventions by leading to formation of tissues that are closer in composition to the native, uninjured tissue. Specific tissue differentiation from different stem cell origins allows versatility in this process across many subtypes of orthopedic injuries. The second article by Jevons et al. addressed the socioeconomic impact of musculoskeletal system as a major source of disability and morbidity, with lacking effective long term treatments resulting in financial and time strains on the health care systems and the patients. The identify pluripotent stem cells as a promising source of in vitro differentiation in regenerative medicine, and foresee future studies applying these practices to tissue engineering versus cell transplantation. The third review by Lovel and Burdick, in similar fashion, assessed current treatment modalities, the options for stem cells and how they can differentiate, and how this can be applied across different musculoskeletal injuries. Unlike the second study this one looked at mesenchymal stem cells from various origins such as bone marrow, synovial and umbilical cord, as well as nasal chondrocytes. They conclude that bone marrow MSCs have shown favorable results in tissue repair and reduction of pain. They do note that further evidence-based clinical trials are necessary to understand the full extent of the efficacy of these therapies. The fourth review by Via et al. is able to identify the promise of MSCs for musculoskeletal injury, and elaborates on the growth factors and mediums necessary for these cells to live and duplicate. However, this study illustrates that the in vitro results that have been observed thus far have not ever been reproduced in vitro in human subjects. They note limitations of animal studies thus far, claiming the tendinopathies that are observed in practice are not reliably reproducible in animal studies, such as acute interventions to study chronic degenerative pathology. For these limitations, they do offer possible solutions to extend the viability of these cells in vivo, through local, sustained release of growth factors to help the differentiation scaffold and cell longevity and viability. The fifth study by Levi et al. is a multicenter study assess the use of human neural stem cells in regenerative purposes for spinal cord injuries.  The analyses of the cohorts did show favorable improvement in upper extremity motor score and graded redefined assessment of strength, sensibility, and prehension, but were unable to clinically evaluate the efficacy due to early study termination. The sixth study by Windt et al. was also a two phase, prospective cohort study of 10 patients with either standard MSC injection versus injection of MSCs with autologous chondrons. At one year there were no identifiable treatment related adverse events, and clinical outcome was statistically significantly improved, including functionality and pain scores, with MRI imaging supporting the integration of these tissues as similar to native tissue with appropriate tissue fiber orientation as the tissue regrows. The final study included by Akgun et al. is similar in nature to the sixth study, but with a two year follow up. They found that mesenchymal stem cell implantation resulted in better outcomes than chondrocyte implantation with functional outcome and subjective scoring in the patients. This study found similar results, with overall better outcomes in the MSC subgroup than the chondrocyte group, but observed favorable outcomes with both modalities.

 

 

Clinical Bottom Line:

While most of the studies accumulated are literature reviews, they are important to the underlying understanding of this up and coming therapeutic modality and therefore the implementation of such practices in patients. Some of the latter studies included hold a higher quality of evidence based on their study design, but lack the sustenance of the literature reviews as they have small study populations and less than ideal patient follow up. The magnitude of effect is hard to assess in such a new intervention, but the results show promising outcomes with the introduction of these therapies in conjuncture with traditional surgical treatment. While such a new, high-tech modality may seem costly, the long term savings in a more effective, definitive treatment can ultimately reduce overall health care costs, even if the addition of this treatment may increase costs in the short term. Such potential for tissue differentiation and the possibility of better tissue matching in vitro in the patient makes this a very applicable treatment option for all patients, as in using their own tissue the risk of rejection or failure is reduced. The clinical bottom line is that the evidence shows extreme potential in this area of regenerative medicine in orthopaedic practice, but there is a significant lack of human studies of reputable design to support the clinical efficacy and reproducibility of this therapeutic option.