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Umbilical cord-derived Wharton’s Jelly for Regenerative Medicine Applications in Orthopedic Surgery: A Systematic Review Protocol

Authors:
  • Università degli Studi di Roma Sapienza

Abstract

Background: Musculoskeletal injuries and conditions affect millions of individuals. These ailments are typically managed by immobilization, physiotherapy or activity modification. Regenerative medicine has experienced tremendous growth in the past decades, especially in musculoskeletal medicine. Umbilical cord-derived Wharton’s Jelly is an exciting new option for such therapies. Wharton’s jelly is a connective tissue located within the umbilical cord largely composed of mesenchymal stem cells and extracellular matrix components, including collagen, chondroitin sulfate, hyaluronic acid and sulfated proteoglycans. Wharton’s Jelly is a promising and applicable biologic source for orthopedic regenerative application. Methods: A systematic search will be conducted in PubMed, ScienceDirect and Google Scholar databases of English, Italian, French, Spanish and Portuguese language articles published to date. References will be screened and assessed for eligibility by two independent reviewers as per PRISMA guidelines. Articles will be considered without exclusion to sex, activity or age. Studies will be included if they used culture-expanded, mesenchymal stem/stromal cells of mesenchymal stem cells and/or connective tissue obtained from Wharton’s Jelly. Studies will be excluded if Wharton’s Jelly is not the sole experimental examined cell type. Placebos, conventional non-operative therapies including steroids injections, exercise and NSAIDs will be compared. The study selection process will be performed independently by two reviewers using a reference software. Data synthesis and meta-analysis will be performed separately for clinical and pre-clinical studies. Discussion: The results will be published in relevant peer-reviewed scientific journals. Investigators will present results at national or international conferences. Trial registration: The Protocol was registered on PROSPERO international prospective register of systematic reviews prior to commencement, CRD42020182487.
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Umbilical cord-derived Whartons Jelly for
Regenerative Medicine Applications in Orthopedic
Surgery: A Systematic Review Protocol
Benjamin J. Main
Beaumont Hospital - Farmington Hills
Josiah A. Valk
Beaumont Hospital - Farmington Hills
Nicola Maffulli
Barts and The London School of Medicine and Dentistry
Hugo C. Rodriguez
University of the Incarnate Word School of Osteopathic Medicine
Manu Gupta
Future Biologics
Ian W. Stone
University of the Incarnate Word School of Osteopathic Medicine
Saadiq F. El-Amin III
BioIntegrate
Ashim Gupta ( ashim6786@gmail.com )
Future Biologics https://orcid.org/0000-0003-1224-2755
Study protocol
Keywords: Regenerative Medicine, Musculoskeletal Injuries, Umbilical Cord, Whartons Jelly, PRISMA
DOI: https://doi.org/10.21203/rs.3.rs-34938/v2
License: This work is licensed under a Creative Commons Attribution 4.0 International License. 
Read Full License
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Abstract
Background: Musculoskeletal injuries and conditions affect millions of individuals.These ailments are
typically managed by immobilization, physiotherapy or activity modication. Regenerative medicine has
experienced tremendous growth in the past decades, especially in musculoskeletal medicine. Umbilical
cord-derived Wharton’s Jelly is an exciting new option for such therapies. Wharton’s jelly is a connective
tissue located within the umbilical cord largely composed of mesenchymal stem cells and extracellular
matrix components, including collagen, chondroitin sulfate, hyaluronic acid and sulfated proteoglycans.
Whartons Jelly is a promising and applicable biologic source for orthopedic regenerative application.
Methods: A systematic search will be conducted in PubMed, ScienceDirect and Google Scholar
databases of English, Italian, French, Spanish and Portuguese language articles published to date.
References will be screened and assessed for eligibility by two independent reviewers as per PRISMA
guidelines. Articles will be considered without exclusion to sex, activity or age. Studies will be included if
they used culture-expanded, mesenchymal stem/stromal cells of mesenchymal stem cells and/or
connective tissue obtained from Whartons Jelly. Studies will be excluded if Whartons Jelly is not the sole
experimental examined cell type. Placebos, conventional non-operative therapies including steroids
injections, exercise and NSAIDs will be compared. The study selection process will be performed
independently by two reviewers using a reference software. Data synthesis and meta-analysis will be
performed separately for clinical and pre-clinical studies.
Discussion: The results will be published in relevant peer-reviewed scientic journals. Investigators will
present results at national or international conferences.
Trial registration: The Protocol was registered on PROSPERO international prospective register of
systematic reviews prior to commencement, CRD42020182487.
Background
Musculoskeletal conditions affect millions of individuals each year and represent a large burden on
healthcare. These ailments are classically managed with immobilization, activity modication, physical
therapy, and pharmacological agents, and surgery when conservative management has failed. These
modalities are limited, often attempting to limit pain rather than addressing the actual pathology [1-7].
Regenerative medicine has undergone tremendous growth during the past few decades, especially in
musculoskeletal medicine [8]. Human stem cells offer regenerative potential, aiming to hasten or reverse
chronic disease in order to restore function [9-11]. Common sources of metabolically available human
stem cells include bone marrow concentrate (BMC), adipose tissue, amniotic tissue, umbilical cord blood
and umbilical cord-derived Wharton’s Jelly [12-17]. Stem cell biologic therapies for the treatment of
musculoskeletal injuries are becoming more common in orthopedic clinical practice. Increased patient
awareness has led to increased demand for biologic therapies [8].
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To date, there is no consensus regarding the most appropriate stem cell source. BMC, PRP, and adipose-
derived stem cells (ADSCs) have received increased scientic attention given their unique properties and
clinical availability. Direct injection therapy has proven benecial in a human model. Bone marrow
mesenchymal stem cells (BMSCs) have limitations associated with increased pain and morbidity from
the bone marrow aspiration procedure [18]. BMC has a limited number of BMSCs, with roughly (0.001-
0.01%) of BMSCs within the BMC [18]. The limited availability and the fact that BMSCs show signs of
early senescence urge to identify and exploit other sources of stem cells [18]. The literature on ADSCs is
limited, with the lack of randomized double-blinded trials and lack of long term follow up observation
being the major contributors [19]. The long-term safety of ADSCs is also yet to be determined [19]. PRP
has been extensively studied, but most of the results are biased, and from poorly designed studies that
favor the publication of positive results [20]. Although safe and promising, PRP still has not shown strong
evidence of ecacy and effectiveness in the human clinical setting [20].
Whartons Jelly is a connective tissue located within the umbilical cord largely composed of hyaluronic
acid and chondroitin sulfate. The chief role of Wharton’s Jelly is to resist torsional and compressive
stresses imposed upon the umbilical vessels during fetal development. Within the Wharton’s Jelly are
primitive mesenchymal stem cells [21]. These perinatal mesenchymal stem cells resemble embryonic
stem cells, but, retain many properties of adult mesenchymal stem cells. Whartons Jelly-derived
mesenchymal stem cells express lower levels of pluripotent markers than embryonic stem cells,
suggesting they are highly multipotent rather than pluripotent [22, 23]. Whartons Jelly contains the
highest concentration of mesenchymal stem cells per milliliter compared to other tissues with rich
extracellular matrix components, including collagen, chondroitin sulfate, hyaluronic acid, and sulfated
proteoglycans [24, 25]. Wharton’s Jelly has also a clinically relevant quantity of growth factors, cytokines
and extracellular vesicles [1]. The large amount of these substances may play a role in reducing
inammation, pain and augment healing of musculoskeletal injuries [1].
Whartons Jelly is easily accessible and available as opposed to other biologics. Every birth presents an
opportunity to harvest these highly multipotent, nutrient rich mesenchymal stem cells. The ease of
collection offers many advantages over current BMC and adipose-derived stem cell harvest, which pose
donor site morbidity. This factor, as well as the attractive expansion properties of umbilical-derived stem
cells and clinically signicant amounts of applicable regenerative substances,make Wharton’s Jelly a
promising source of mesenchymal stem cells for orthopedic regenerative application [1, 26]. Considering
the lack of clarity regarding the use of Wharton’s jelly, methodological factors, clinical translation and
outcome measurement, a systematic review is required to synthesize and evaluate the quality of the
available evidence regarding the safety and ecacy of Whartons jelly for regenerative medicine
applications in orthopedic surgery. The primary objective of this review is to report the clinical, structural
and functional outcomes of the applications of Wharton’s jelly for regenerative medicine in orthopedic
surgery. The secondary objective is to identify methodological characteristics associated with application
outcomes.
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Methods
The protocol was registered on the PROSPERO international prospective register of systematic reviews,
registration number CRD42020182487. The systematic review will follow the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) statement and guidelines [27, 28].
Eligibility Criteria
The PICOS (Population, Intervention, Comparison, Outcome, Study Design) framework will be used as a
template for dening eligibility criteria for literature search [29]. Characteristics for clinical studies are as
follow:
Population
Research involving animal and human models (clinical studies as well as
in vitro
research) will be
considered for review, without exclusion relating to sex or age. Basic science studies must include human
cells isolated from a living model. Studies meeting eligibility criteria will apply to acute orthopedic
musculoskeletal injury, chronic orthopedic musculoskeletal conditions, or an articial disease model.
Articles will be excluded if they do not relate to orthopedic intervention.
Intervention
Research meeting inclusion criteria will involve the use of mesenchymal stem cells and/or connective
tissue obtained from Whartons Jelly. Studies will be excluded if Whartons Jelly is not the experimental
examined cell type. Studies involving umbilical derived stem cells will be excluded unless the study
species the use of Wharton’s Jelly. Studies will be excluded if they report the use of Whartons Jelly
derived mesenchymal stem cells in combination with other cell populations.
Comparison
Comparators considered will include placebos, non-injury models, acute injury models, non-injury models,
and gold standard treatments for orthopedic injury.
Outcomes
For basic scientic research, studies relating to human musculoskeletal injury via histological or
biochemical measures will be included. For clinical research, studies pertaining to human or animal
orthopedic musculoskeletal injury via histological and/or biochemical measures and functional scores
(pain, activity, quality of life, etc.) will be included.
Study Design
Observational studies (cohort, cross-sectional and case-controlled prospective or retrospective studies) or
randomized controlled trials comparing outcomes of connective tissue derived from Wharton’s Jelly with
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control, experimental therapy, or gold standard treatment at any follow up period will be included.
Systematic reviews will only be examined to identify further studies for inclusion, and results of meta-
analysis will not be included in the analysis. With regard to publication year, all studies published to date
will be included.
Information Sources
A systematic search will be conducted in PubMed, ScienceDirect and Google Scholar databases of
English, Italian, French, Spanish and Portuguese language articles published before May 2020.
Secondary searching of reference lists of key articles and reviews will be undertaken to identify any
additional studies potentially missed in electronic search.
Search
The search and selection process will be based on the PRISMA checklist and ow diagram based on the
eligibility and inclusion criteria previously outlined. A web-based reference software system (RefWorks)
will be used for data management.
Study Selection
The study selection process will be performed independently by two reviewers. Screening of abstracts will
be performed, and full text articles will be retrieved and uploaded to the reference software. A thorough
secondary screening will be performed independently by two reviewers. The secondary screening of the
full text articles will eliminate studies that do not meet inclusion criteria.
Data Collection
Data extraction from articles that meet inclusion criteria will be performed by two independent reviewers.
Data extracted and synthesized will include authors, publication year, study design, group controls, group
interventions, outcome measurement, and outcome assessment. Customized forms will be used in the
data extraction and collection process. The primary authors will be contacted via email for any
information necessitating clarication.
Data Items
Relevant items of population, problem, intervention, comparison, and outcome will be extracted and
included. For basic scientic research, relevant histological and/or biochemical measures will be
included. For clinical research, all histological measures, biochemical measures and functional scores
will be included.
Risk of bias
Multiple tools will be used to assess the risk of bias for included studies. The Systematic Review Centre
for Laboratory Animal Experimentation (SYRCLE) risk of bias tool will be applied to animal studies [30].
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Ten domains will be addressed related to selection bias, performance bias, detection bias, attrition bias,
reporting bias, and other biases. The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I)
tool will be used to assess observational and quasi-randomized studies [31]. Seven domains will be
utilized to assess risk including: confounding, participant selection bias, classication bias, deviation
bias, bias due to missing data, outcome measurement bias, and bias in selection of reported results.
Studies will be judged to have no information or a low, moderate, serious, or critical risk of bias. For
randomized control trials, the Risk of Bias 2 (RoB 2) tool will be used to establish risk of bias [32]. Five
domains including biases arising from the randomization process, due to deviations from intended
interventions, due to missing outcome data, in measurement of the outcome, and in selection of the
reported result will be analyzed. Overall risk of bias will be determined to be low, some concerns, or high.
All included studies will be independently scored by two reviewers, and consensus reached by discussion.
Data synthesis and meta-analysis
Data synthesis and meta-analysis will be performed separately for clinical and pre-clinical studies,
following the guidelines published by Hooijmans et al [30]. Given the sparsity of homogenous research, a
qualitative analysis of common outcome variables will be conducted. Subgroups chosen for analysis will
include cells derived from Wharton’s Jelly versus experimental therapy and/or control. Results of meta-
analyses extracted data will be summarized in tables and narrative interpretation provided, with
emphasis on outcome measures.
Discussion
The results of this review will be published in a relevant scientic journal or presented at national or
international conferences (‘Publications’) by the Investigators.
Documenting protocol amendments
Protocol amendments and updates will be documented via PROSPERO online register. The nature of the
changes made will be recorded, dated and accessible along with the most recent version within the record
audit trail under the systematic review protocol registration number CRD42020182487.
List Of Abbreviations
ADSCs Adipose-derived stem cells
BMC Bone marrow concentrate
BMSCs Bone marrow mesenchymal stem cells
PICOS Population, Intervention, Comparison and Outcome
PRISMA     Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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PRP        Platelet-rich plasma
ROBINS-I   Risk Of Bias in Non-randomized Studies- of Interventions
SYRCLE     Systematic Review Centre for Laboratory Animal Experimentation
Declarations
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Availability of data and materials
The results of this review will be published in a relevant scientic journal or presented at national or
international conferences (‘Publications’) by the Investigators.
Competing interests
The authors declare that they have no competing interests.
Funding
This research received no specic grant from any funding agency in the public, commercial or not-for-
prot sectors.
Authors’ contributions
AG and NM contributed to the review concept and study design. BJM, JAV and AG provided input for the
review. BJM and JAV provided input to the development of search strategies and methodologies for the
literature review. BJM, JAV, HCR, MG, IWS, NM, SFE and AG drafted the review protocol. All authors
provided feedback and approved the nal protocol. AG is the guarantor of the review.
Acknowledgments
Not Applicable
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Objective: To investigate the effect of phase polarity and charge balance of spinal cord stimulation (SCS) waveforms on pain behavior and gene expression in a neuropathic pain rodent model. We hypothesized that differing waveforms will result in diverse behavioral and transcriptomics expression due to unique mechanisms of action. Materials and methods: Rats were implanted with a four-contact cylindrical mini-lead and randomly assigned to two control (no-pain and pain model) and five test groups featuring monophasic, as well as charge-unbalanced and charge-balanced biphasic SCS waveforms. Mechanical and cold allodynia were assessed to measure efficacy. The ipsilateral dorsal quadrant of spinal cord adjacent to the lead was harvested post-stimulation and processed to determine gene expression via real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Gene expression, SCS intensity (mA), and behavioral score as percent of baseline (BSPB) were statistically analyzed and used to generate correlograms using R-Studio. Statistical analysis was performed using SPSS22.0, and p < 0.05 was considered significant. Results: As expected, BSPB was significantly lower for the pain model group compared to the no-pain group. BSPB was significantly improved post-stim compared to pre-stim using cathodic, anodic, symmetric biphasic, or asymmetric biphasic 1:2 waveforms; however, BSPB was not restored to Sham levels. RT-PCR analysis showed that eight genes demonstrated a significant difference between the pain model and SCS waveforms and between waveforms. Correlograms reveal a linear correlation between regulation of expression of a given gene in relation to mA, BSPB, or other genes. Conclusions: Our results exhibit that specific SCS waveforms differentially modulate several key transcriptional pathways that are relevant in chronic pain conditions. These results have significant implications for SCS: whether to move beyond traditional paradigm of neuronal activation to focus also on modulating immune-driven processes.
Article
Over the past decade, there has been an increased interest in the use of biologic therapies in sports medicine. Although these technologies are in relatively early stages of development, there have been substantial increases in marketing, patient demand, and clinical utilization of biologics, including platelet-rich plasma, bone marrow aspirate concentrate, and other cell-derived therapies. Direct-to-consumer marketing of biologics has also proliferated but is largely unregulated, and clinicians must accurately convey the safety and efficacy profiles of these therapies to patients. Because most insurance companies consider biologic treatments to be experimental or investigational for orthopaedic applications given the lack of high-quality evidence to support their efficacy, patients receiving these treatments often make substantial out-of-pocket payments. With a range of treatment costs among centers offering biologics, there is a need for appropriate and sustainable pricing and reimbursement models. Clinicians utilizing biologics must also have a thorough understanding of the recently clarified Food and Drug Administration guidelines that regulate the clinical use of cell and tissue products. There is a lack of consensus on the optimal preparation, source, delivery method, and dosing of biologic therapies, which has been exacerbated by a lack of sufficient experimental detail in most published studies. Future research must better identify the biologic target of treatment, adhere to better standards of reporting, and better integrate researchers, industry, and regulatory bodies to optimize applications.
Article
Articular cartilage is a remarkable tissue whose sophisticated composition and architecture allow it to withstand complex stresses within the joint. Once injured, cartilage lacks the capacity to self-repair, and injuries often progress to joint wide osteoarthritis (OA) resulting in debilitating pain and loss of mobility. Current palliative and surgical management provides short-term symptom relief, but almost always progresses to further deterioration in the long term. A number of bioactive factors, including drugs, corticosteroids, and growth factors, have been utilized in the clinic, in clinical trials, or in emerging research studies to alleviate the inflamed joint environment or to promote new cartilage tissue formation. However, these therapies remain limited in their duration and effectiveness. For this reason, current efforts are focused on improving the localization, retention, and activity of these bioactive factors. The purpose of this review is to highlight recent advances in drug delivery for the treatment of damaged or degenerated cartilage. First, we summarize material and modification techniques to improve the delivery of these factors to damaged tissue and enhance their retention and action within the joint environment. Second, we discuss recent studies using novel methods to promote new cartilage formation via biofactor delivery, that have potential for improving future long-term clinical outcomes. Lastly, we review the emerging field of orthobiologics, using delivered and endogenous cells as drug-delivering “factories” to preserve and restore joint health. Enhancing drug delivery systems can improve both restorative and regenerative treatments for damaged cartilage. Statement of significance Articular cartilage is a remarkable and sophisticated tissue that tolerates complex stresses within the joint. When injured, cartilage cannot self-repair, and these injuries often progress to joint-wide osteoarthritis, causing patients debilitating pain and loss of mobility. Current palliative and surgical treatments only provide short-term symptomatic relief and are limited with regards to efficiency and efficacy. Bioactive factors, such as drugs and growth factors, can improve outcomes to either stabilize the degenerated environment or regenerate replacement tissue. This review highlights recent advances and novel techniques to enhance the delivery, localization, retention, and activity of these factors, providing an overview of the cartilage drug delivery field that can guide future research in restorative and regenerative treatments for damaged cartilage.
Article
In orthopedic sports medicine, amniotic-derived products have demonstrated promising preclinical and early clinical results for the treatment of tendon/ligament injuries, cartilage defects, and osteoarthritis. The amniotic membrane is a metabolically active tissue that has demonstrated anti-inflammatory, antimicrobial, antifibrotic, and epithelialization-promoting features that make it uniquely suited for several clinical applications. Although the existing clinical literature is limited, there are several ongoing clinical trials aiming to elucidate the specific applications and benefits of these products. This article reviews the current amniotic-derived treatment options and the existing literature on outcomes, complications, and safety profile of these products for use in sports medicine.
Article
Platelet-rich plasma (PRP) is a promising treatment for musculoskeletal maladies and clinical data to date have shown that PRP is safe. However, evidence of its efficacy has been mixed and highly variable depending on the specific indication. Additional future high-quality large clinical trials will be critical in shaping our perspective of this treatment option. The heterogeneity of PRP preparations, both presently and historically, leads sweeping recommendations about its utility impossible to make. This heterogeneity has also made interpreting existing literature more complicated.
Article
The meniscal tear treatment paradigm traditionally begins with conservative measures such as physical therapy with referral for operative management for persistent or mechanical symptoms. As a result, the partial meniscectomy is performed more than any other orthopedic procedure in the United States. This treatment paradigm has shifted as recent literature supports the attempt to preserve or repair the meniscus whenever possible given its importance for the structural integrity of the knee joint and the risk of early osteoarthritis associated after meniscus excision. Choosing an appropriate management strategy depends on multiple factors such as patient demographics and location of the tear. Physical therapy remains a first line treatment for knee pain secondary to meniscus tear and should be pursued in the setting of both acute and chronic knee pain. Furthermore, there is a growing amount of evidence showing that elderly patients with complex meniscus tears in the setting of degenerative arthritis should not undergo arthroscopic surgery. Direct meniscus repair remains an option in ideal patients who are young, healthy, and have tears near the more vascular periphery of the meniscus but are not suitable for all patients. Use of orthobiologics such as platelet rich plasma and mesenchymal stem cells show promise in augmenting surgical repairs or as stand-alone treatments though research for use in meniscal tear management is limited.