Regenerative medicine approaches for children with cerebral palsy: a systematic review of clinical safety and effectiveness

Introduction

Cerebral palsy (CP) is the leading cause of physical disability in children (1). It results from non-progressive damage to the developing fetal or infant brain, leading to persistent abnormalities in movement and posture, which often affect perception and sensation as well. Despite advances in obstetric and neonatal care, the global incidence of CP has remained largely stable, with current management primarily focused on symptom relief, emphasizing spasticity reduction, skeletal correction, and intensive rehabilitation to improve functional outcomes and participation (2,3). These traditional approaches, while important, have limited ability to reverse existing brain injuries or radically alter the course of the underlying disease, creating an urgent need for therapies that can repair or regenerate damaged neural tissue and potentially promote functional recovery (4,5).

Regenerative medicine for pediatric CP is a contemporary but experimental area, whereby the most extensively studied modalities include umbilical cord (UC)-derived products such as allogeneic cord blood (ACB), cord tissue mesenchymal stem cells (CTMSCs), and Wharton’s jelly mesenchymal stem cells (WJ-MSCs). Bone-marrow (BM)-derived products include bone marrow mesenchymal stem cells (BMMSCs), bone marrow mononuclear cells (BMMNCs), and neural stem cell (NSC)-like. Moreover, adjunctive biologicals such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) were also used (6-8).

Trials focus on processes such as neuroinflammation, compromised connectivity, and white-matter damage, aiming to augment neuroplasticity during essential developmental periods (9,10). Early clinical studies suggest potential benefits in gross motor and functional outcomes, but reported effects vary widely across cell type, dose, route of administration, and follow-up duration (11,12). However, these methods are predominantly in preclinical stages or early-phase human trials for pediatric CP. Traditional therapies like physiotherapy, occupational, speech therapy, and neurosurgery remain the evidence-based standard of care and typically constitute the foundation for any regenerative strategy (13).

Systematic reviews and meta-analyses of randomized controlled trials (RCTs) demonstrate that stem cell therapy, particularly involving MSCs or combined stem cell protocols, correlates with statistically significant enhancements in gross motor function measure (GMFM) and composite functional scores over a duration of 3 to 12 months (14,15). Conversely, therapies derived from cord blood exhibit encouraging data, including controlled trials and crossover studies that reveal dose-proportional enhancements in motor function, and occasionally in social and behavioral outcomes, in young children, particularly when integrated with intensive rehabilitation or EPO (16,17). MSCs appear to be less effective than umbilical cord blood (UCB) during the chronic damage phase, and the optimal cell type, dosage, timing, and frequency of injections remain undefined (18).

Given the rapid growth of clinical research in this field, there is an immediate necessity for a comprehensive evaluation that rigorously assesses safety, scientific quality, and clinical relevance. Although several systematic reviews and meta-analyses have evaluated specific stem cell-based therapies in CP, most have focused on selected cell types or limited study designs. There remains a lack of comprehensive synthesis across different stem cell-based regenerative approaches, particularly integrating safety, methodological quality, and clinical applicability. This review aims to address this gap and provide a structured overview to inform clinical decision-making and future research directions. This systematic review intends to evaluate the effectiveness and safety of regenerative medicine therapy in pediatric patients with CP, focusing on study design characteristics, outcome measures, and issues related to the quality of evidence. We present this article in accordance with the PRISMA reporting checklist (19) (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0249/rc).

Methods

Study design and protocol registration

This research was performed as a comprehensive review of regenerative medicine therapies for children with CP. The protocol was prospectively registered with the International Prospective Registry of Systematic Reviews (PROSPERO) under registration number CRD420251083077.

Search strategy

A comprehensive literature search was conducted in July 2025 across the databases including PubMed (National Library of Medicine), ScienceDirect, Cochrane Library, and Web of Science and covered the period from January 2010 to January 2025. The search was limited to studies published from 2010 onwards to reflect contemporary clinical protocols, advances in stem cell processing, and improved trial design, ensuring relevance to current clinical practice.

In addition, Medical Subjects Heading (MeSH database) and keyword searches for non-MeSH data were conducted. The keywords employed for the search were (“cerebral palsy”[MeSH Terms] OR “cerebral palsy” OR “CP”) AND (“regenerative medicine” OR “stem cell therapy” OR “mesenchymal stem cells” OR “cord blood” OR “umbilical cord blood” OR “bone marrow cells” OR “neural stem cells” OR “olfactory ensheathing cells”) AND (“pediatric” OR “child” OR “children” OR “infant” OR “adolescent”) Filters: English, Publication date from 2010/01/01 to 2025/01/01. A complete search strategy for data base, including all search terms, Boolean operators, and applied filters, is provided in Table S1.

Study selection and eligibility criteria

This review included RCTs, non-randomized interventional studies, prospective or retrospective cohort studies, and case series (≥3 participants) that published in English. We excluded case reports, preclinical or animal studies, narrative or systematic reviews, editorials and opinion pieces, conference abstracts without full data, studies not published in English, non-open access and articles lacking extractable outcome data. To minimize bias, preclinical and case-report evidence were deliberately excluded from synthesis and interpretation.

PICO was used to define the inclusion criteria as follows:

• Population/patients: children (males and females) diagnosed with CP, including all types.
• Intervention/exposure: this review summarizes data on regenerative medicine Regenerative medicine interventions, including: UC-derived products, MSCs (any source), BM-derived cellular therapies, and biological adjuncts administered with regenerative products (e.g., EPO, G-CSF).
• Comparators: standard care, placebo, sham procedures, or no comparator. Non-comparative studies were included but analyzed separately.
• Outcomes: at least one of the following: motor function (e.g., GMFM), cognitive or developmental outcomes, and adverse events and safety outcomes.

Three reviewers independently screened titles and abstracts using predefined criteria. Full texts were assessed for all studies that appeared eligible or required clarification. Disagreements were resolved through discussion with a fourth reviewer. Duplicates were removed prior to screening. Reasons for exclusion at the full-text stage were documented. The final selection data is summarized in the PRISMA flow diagram (Figure 1).

Figure 1 PRISMA flow diagram for search strategy process. PICO, Population, Intervention, Comparison, and Outcome.

Data extraction

Data extraction was done by two reviewers using a standardized form. Extracted variables included: name of the first author, year of publication, country, study design, study aims, sample size, and age of studied individual. Type of regenerative medicine, source of it, treatment method, administration route and frequency, outcome, and adverse events were also extracted. Disagreements were resolved through discussion, and when necessary, consultation with a third reviewer.

Synthesis of the evidence

To determine the research’ rigorousness of methodology, randomized trials were evaluated using the Cochrane RoB-2 tool, while non-randomized studies were assessed with ROBINS-I (20). Two reviewers conducted evaluations independently, with disagreements resolved by consensus. Each domain was judged as low, some concern, or high risk (RoB-2), and low, moderate, serious, or critical risk (ROBINS-I). Results are summarized in graphical formats and table (Figure 2 and Tables S2,S3).

Figure 2 Regenerative medicine distribution according to countries in the involved studies (n, %).

Data synthesis

Given substantial heterogeneity across trials in study design, intervention type, dosing regimens, outcome measures, and follow-up duration, a narrative synthesis was performed. Where studies were sufficiently homogeneous regarding design, outcome definition, and timing of assessment, results were qualitatively compared. Effect estimates were not pooled when methodological variability or bias risk suggested that meta-analysis would be misleading. Outcomes are therefore presented by: intervention class, study design category, and outcome domain (motor, cognitive, and safety). Particular emphasis was placed on clinically meaningful change thresholds, not only statistical significance.

Results

Study selection

A database search yielded 410 records. After removing duplicate records and examining titles and abstracts, 61 full articles were evaluated to determine their eligibility for inclusion. An additional 22 records were identified through clinical trial records and reference checks. Ultimately, 18 studies met the inclusion criteria and were included in the final analysis (21-38). Figure 1 (PRISMA flowchart) summarizes the selection process.

Although regenerative medicine includes tissue engineering and biomolecule-based therapies, no eligible clinical trials on tissue engineering or biomolecule-based regenerative therapies were identified.

Study characteristics

A summary of the 18 included studies is presented in Table 1. These comprise 10 randomized controlled (21-23,25-30,32), three open-label clinical trial (24,31,34), and five non-randomized studies (33,35-38). The majority of studies were conducted in China, Korea, and the United States, with publication dates ranging from 2012–2025 (Figure 3). Sample sizes varied considerably, from small exploratory groups to multicenter randomized trials. Funding sources were reported in 16 studies, with the majority supported by institutional or governmental funding, while one study did not disclose funding information (36), and one study disclosed non-funded status (38).

Figure 3 Risk of bias assessment of the studies using RoB2 and ROBIN 1 tools.

Participant characteristics

Across the 18 studies, a total of 1,087 children with CP were included. Age at enrollment ranged from 6 months to 17 years, although several studies did not report detailed phenotype or severity stratification. The most common diagnoses were spastic and mixed CP, with considerable variability in basic functions. Reporting comorbidities and prior treatments was inconsistent across studies.

In terms of exposure: 73.5% (n=799) of all patients received UC-derived products, whereas 20.3% (n=221) were treated by BM-derived products, 1.8% (n=20) used mixed UC or BM-derived products, and 4.3% (n=47) received G-CSF.

Treatment response may vary according to patient characteristics such as age, severity of CP (e.g., GMFCS level), and underlying etiology. However, most included studies did not provide sufficient data to enable formal subgroup analysis.

Types of interventions and delivery approaches

Regenerative medicine strategies included: UC blood mononuclear cells, MSCs (UC, Wharton’s jelly, or bone marrow), NSC-like preparations, combination protocols incorporating EPO or G-CSF. About 53% (n=576) of the participants in eight studies received area under the curve (AUC) origins MSC (21,24,25,27,28,33,34,36). Across trials, MSCs were most commonly sourced from UC-derived products (including Wharton’s jelly) in 13 studies (21-28,32-34,36,37), and BM-derived products (including NSC-like cells) were derived from autologous bone marrow MSCs and also used in four studies (30,31,35,38), while one study was including G-CSF (29). The products either used alone or in combination with adjunctive agents such as EPO or G-CSF, reflecting substantial heterogeneity in regenerative medicine type and method. Regenerative medicine interventions identified in the included studies primarily comprised cell-based therapies using MSCs and UC-derived products, delivered via various routes and dosing regimens. Across the included studies, intravenous administration was the most commonly used route (n=10 studies), followed by intrathecal delivery (n=6 studies), while a small number of studies employed combined or alternative administration approaches. Regarding dosing strategies, most studies administered cell-based therapies either as a single infusion (n=7) or as repeated doses at defined intervals (n=11), ranging from weekly to monthly schedules. Dose reporting varied substantially across studies, with cell doses typically expressed per kilogram of body weight and ranging from approximately 10⁶ to 10⁸ cells/kg depending on the intervention type and protocol. This variability in administration route, dosing frequency, and dosage reflects the experimental nature of current regenerative therapies and contributes to the heterogeneity observed across studies.

The treatment was often combined with standard rehabilitation, typically included physiotherapy, occupational therapy, and speech therapy, although intensity and duration varied across studies and were inconsistently reported.

Functional outcomes (GMFM and related measures)

The GMFM score was the most consistently reported mobility outcome. In all studies, UC-derived therapies, particularly cord blood alone or in combination with EPO, demonstrated moderate improvements in overall mobility performance, often exceeding the thresholds established for the minimum clinically significant difference in several trials. UC-derived MSCs approaches generally achieved clinically significant but uneven gains, while BM-derived cell products achieved more modest improvements. However, the interpretation is limited by differences in baseline functional status, the mixed application of blinded outcome assessment, variations in follow-up periods, and limited consistency in reporting adjusted versus raw GMFM scores. Because of these differences, the results were pooled qualitatively rather than statistically. Several randomized trials reported statistically significant improvements in GMFM scores compared with controls (P<0.05), although effect sizes and confidence intervals were inconsistently reported across studies.

Risk of bias

Risk of bias varied considerably across study designs. Ten studies analyzed using RoB-2 exhibited a low to moderate risk of bias across major domains, although allocation concealment and blinding were occasionally unclear (21-23,25-30,32). Observational and open-label study designs inherently carry a higher risk of confounding and performance bias (24,31,33-37). Outcome reporting was generally complete, with limited attrition; however, selective reporting of favorable outcomes could not be excluded. The visualization of risk of bias assessment was demonstrated with colorblind-friendly graphical summaries and detailed tables provided in Tables S2,S3 after using online website (20).

Safety and adverse events

Safety reports were available for nearly all studies. Overall, regenerative therapies were well tolerated in all interventions. The most common side effects included transient fever, headache, gastrointestinal disturbances, mild respiratory infections, back pain, or transient neurological discomfort following intrathecal injection. A few serious events were reported, including seizure exacerbations in isolated cases and one death attributed to a cause unrelated to the intervention. No treatment-related malignancies, transplant reactions, or ectopic tissue formation were reported during the available follow-up period. However, long-term monitoring remains limited.

Discussion

This systematic review evaluated current evidence regarding regenerative medicine interventions in children with CP. Despite the diversity of the interventions, most protocols target overlapping mechanisms: endocrine modulation of inflammation, neuroprotection, promotion of axonal growth and synaptic plasticity, and support for regeneration rather than true cell replacement, which is consistent with the observed functional gains without clear evidence of structural regeneration in most trials (9,10,39). Reviews describing improved motor function, cognition, and balance after autologous and allogeneic stem cell therapy, using intravenous and spinal routes, support the hypothesis that systemic and immunomodulatory and paracrine mechanisms are the main axis, with the route of administration primarily influences the distribution and bioavailability of therapeutic cells, rather than fundamentally altering their mechanism of action (40,41). These observations are consistent with findings from other neurological conditions, where the route of stem cell administration influences distribution and bioavailability without fundamentally altering the underlying mechanism of action. However, direct evidence specific to CP remains limited.

The dataset allows only cautious comparative inferences, but some patterns emerge when contrasting UC-derived and BM-derived products. UC-derived interventions tend to be allogeneic, logistically scalable, and often combined with immunomodulators or EPO, while BM-derived approaches are frequently autologous, reliant on harvesting procedures, and more often delivered intrathecally. Intravenous administration predominates in UC-based trials and appears to offer a favorable safety profile with mainly mild infusion reactions, whereas intrathecal protocols, although generally safe, report more procedure-related events such as transient headaches, back pain, and irritability, which must be balanced against the theoretical advantage of higher cerebrospinal exposure, which supposed that increased cerebrospinal fluid exposure in humans is potentially beneficial as it delivers a greater concentration of free medication to the brain and spinal cord targets while minimizing systemic exposure, hence enhancing central efficacy and reducing peripheral toxicity (42,43). In this review, dose and frequency variability prevented a formal comparison, and the lack of standardized dose-response models highlights the experimental nature of current interventions and underscores the need for standardized dosing and reporting practices.

A common characteristic of several studies is the use of standardized assessments like the GMFM scale in conjunction with more comprehensive neurodevelopment or cognitive evaluations; however, the clinical interpretation of significant improvement differs significantly. In some RCTs, statistically significant improvement on the GMFM scale or cognitive indices compared with placebo or natural history were associated with neuroimaging changes, such as improved white matter connectivity or myelination, indicating that the observed improvements likely represent significant biological plasticity instead of simple measurement interference (22,25,26). Nevertheless, some open-label and retrospective studies indicate functional improvements without rigorous controls, suggesting that combined intensive rehabilitation, increased caregiver involvement, or regression to the mean may enhance the reported treatment effects (34,36). The sustainability of benefits is a significant data gap as some extension and follow-up studies indicate continuing, even gradual improvement over 1 to 2 years post-initial injection, in particular in protocols integrating UCB and EPO. However, it remains unclear whether this represents an isolated initial stimulus for neuroplasticity or a continuous response to successive treatment sessions.

Across 18 included studies encompassing diverse designs and cell sources, most interventions reported improvements in gross and fine motor function, balance, spasticity, cognition, and broader functional domains, particularly when regenerative therapies were combined with conventional rehabilitation (22,26). These benefits were observed with UC-derived products, BM-derived products, and adjunctive biologicals such as EPO or G-CSF, though effect sizes and outcome measures varied widely. Importantly, several randomized, placebo-controlled trials suggested that higher cell doses and combination protocols, such as UCB plus EPO, that may yield superior motor and cognitive outcomes compared with single-modality treatment or placebo (21,24,25). The analyzed studies collectively emphasize the significance of dosage but still have not determined an individual therapeutic window or limit. Increased total doses of nuclear cells and greater quantities of continuously administered MSCs are associated with favorable outcomes (21,22,26,30,31,33,36,37). Trials specifically designed to investigate the dose-effect relationship, including those utilizing multiple injections of Wharton’s mesenchymal stem cells, strengthen the concept of a cumulative or limiting effect. Simultaneously, intensification is limited by safety, infusion accessibility, and production capability, indicating the importance of accurate pharmacodynamic modeling and consistent efficacy testing for all experimental therapies (44).

In the included studies, side effects were generally mild and resolved spontaneously. Serious complications were uncommon and generally not associated with the intervention. Nonetheless, the absence of regular, long-term monitoring constitutes a significant deficiency, especially with the risks of immune system sensitization, abnormal tissue development, and cancer. Consequently, dependable documentation and prolonged monitoring are essential prior to the consideration of routine clinical use.

Despite the findings of the included studies, many suffer from limitations due to their use of open-ended, non-randomized, retrospective, or single-group designs, increasing the potential for selection bias, placebo effects, and confounding from concurrent rehabilitation or supportive therapies. Furthermore, the prevalence of short- and medium-term follow-up, inconsistent reporting of imaging or correlations with vital signs, and inconsistent handling of adverse events hinder accurate assessment of the robustness and potential for observed mechanical improvement. Patient age, type and severity of CP, and co-morbidities likely influence response; however, most trials were not adequately controlled for subgroup analyses. Many approaches focused primarily on younger children (specifically, those under 6 years of age), thus emphasizing the stages of increased neuroplasticity, while others included broader age groups up to adulthood, neglecting age-related influences. Given the sustained benefits observed in severely disabled children in some studies, as well as the marked improvement in cognition, communication, and attention, future trials should carefully stratify participants according to gross motor function classification system level, cause, and baseline neurodevelopmental profile to identify phenotypes that have the greatest minimal benefit from regenerative therapies.

This review has several limitations. First, the exclusion of non–open access studies may have introduced selection bias. Second, the absence of meta-analysis limits quantitative synthesis and prevents estimation of pooled effect sizes. Third, substantial heterogeneity in study design, intervention protocols, and outcome measures limits comparability across studies. Finally, publication bias was not formally assessed. The overall evidence base is limited by small samples, and frequent use of non-randomized designs; yet even the better-designed randomized trials face challenges such as incomplete blinding of caregivers and therapists, limited concealment of allocation, and potential unmasking due to infusion reactions or procedural differences. The predominance of non-randomized and open-label designs, along with identified risks of bias, reduces confidence in the observed treatment effects and underscores the need for cautious interpretation. Moreover, outcome reporting is often selective, with adverse events variably attributed, underlining the importance of harmonized adverse event taxonomies and mandatory long-term follow-up registries, particularly given the theoretical risks of ectopic tissue formation, immune sensitization, or late-onset malignancy (45-47). Currently, these approaches should be considered complementary to, not replacements for, established rehabilitation strategies. Their implementation in routine clinical practice requires well-designed, randomized, multicenter trials with standardized protocols, accurate patient classification, and long-term follow-up to demonstrate their sustainability, safety, and cost-effectiveness. Until such data are available, their clinical use should be limited to ethically compliant research settings. Although formal subgroup analysis was not feasible, qualitative comparison suggests that variability in cell source, administration route, and adjunctive therapies may contribute to differences in clinical outcomes.

Conclusions

In conclusion, regenerative medicine approaches for treating CP show promising functional improvement and reassuring safety in the short term, particularly for UC-derived therapies. However, the varying quality of studies and limited long-term efficacy data preclude definitive recommendations regarding the optimal cell type, dosage, or route of administration. Although several studies suggest potential functional improvements, the current evidence remains preliminary and should not be interpreted as definitive clinical effectiveness. At present, regenerative therapies for CP should be considered experimental and limited to well-designed clinical trials. These findings do not support routine clinical implementation but may guide future trial design and patient selection.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0249/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0249/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0249/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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