Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy

Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy Gülşen Köse, Ayberk Akat, Olga Nehir Öztel, Çağatay Öztürk, Merve Cemil, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7202210/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Cerebral palsy is a non-progressive neurodevelopmental disorder often caused by hypoxic ischemic encephalopathy or intracranial hemorrhage, resulting in motor dysfunction and spasticity. While current treatments focus on symptomatic relief, mesenchymal stem cell therapy has emerged as a promising regenerative strategy with neuroprotective and neurorestorative potential. Objective To evaluate the functional and neurological outcomes following umbilical cord-derived mesenchymal stem cell therapy in four pediatric patients with spastic cerebral palsy. Methods This multicenter case series included four children diagnosed with cerebral palsy secondary to hypoxic ischemic encephalopathy or intracranial hemorrhage. Each patient received six sessions of cell therapy via intrathecal, intravenous, and intramuscular routes. Clinical assessments were performed before and after therapy using the Modified Ashworth Scale, Motricity Index, Trunk Control Test, and Medical Research Council Muscle Strength Scale. Results All patients demonstrated improvements in at least one clinical domain. Three patients showed reduced spasticity, improved trunk control, and increased muscle strength. Functional motor scores improved remarkably in most cases, particularly in sit-to-stand transitions and voluntary limb movements. One patient, despite unchanged spasticity scores, exhibited functional gains in posture, head control, and cognitive-emotional interactions. No adverse events were reported in any of the participants. Conclusion Mesenchymal stem cell therapy was well-tolerated and associated with functional improvements and reduced spasticity in children with spastic cerebral palsy at the end of 10–12 months follow-up. These findings support the potential of mesenchymal stem cell-based interventions in pediatric neurorehabilitation and underscore the need for further large-scale trials to validate efficacy, explore cost-efficiency, and enable global accessibility. Cerebral Palsy Mesenchymal Stem Cells Motor Function Spasticity Stem Cell Therapy Figures Figure 1 1. Introduction Cerebral palsy (CP) represents a group of permanent, non-progressive neurological disorders that affect movement, muscle tone, and posture, resulting from damage to the developing brain, most commonly before or during birth [ 1 ]. Recent epidemiological studies have given revised understanding of the worldwide CP prevalence. Reflecting improvements in perinatal and neonatal care, it has been revealed that the birth prevalence of CP in high-income countries has dropped to almost 1.6 per 1,000 live births, while low and middle-income countries show a higher frequency; estimates range from 3.4 per 1,000 live births, underscoring disparities in healthcare access and quality [ 1 – 3 ]. Though non-progressive, the clinical symptoms of CP sometimes cause gradual musculoskeletal problems that over time greatly affect functional independence and quality of life. Often resulting in joint contractures and gait abnormalities, spastic CP is the most common type and is defined by increased muscle tone, exaggerated reflexes, and impaired voluntary movement [ 1 , 4 ]. CP is a disorder that should be managed through a multidisciplinary approach aimed at improving motor function, reducing complications, and enhancing quality of life. Conventional interventions include physical and occupational therapy to enhance mobility and daily functioning, speech therapy for communication difficulties, and medications such as baclofen or botulinum toxin to manage spasticity [ 5 , 7 ]. To treat severe muscle tightness or skeletal abnormalities, orthopedic surgeries or selective dorsal rhizotomy may be used [ 8 , 9 ]. However, these treatments do not address the underlying neurological damage; instead, they mainly provide symptomatic relief. Mesenchymal stem cell (MSC) therapy is one of the emerging treatments being investigated for its potential for addressing neural injury and enhancing motor outcomes in patients with CP [ 10 , 11 ]. Due to their numerous regenerative attributes, MSCs have become an appealing therapy option for CP. MSCs have potent immunomodulatory and anti-inflammatory properties that may reduce the neuroinflammation associated with CP. Furthermore, MSCs secrete neurotrophic factors that facilitate neural repair and functional recovery by enhancing synaptic plasticity, promoting neurogenesis, and supporting neuronal survival [ 10 – 13 ]. Clinical evidence has shown that MSC therapy has an impressive safety record and can significantly improve gross motor function and overall neurological outcomes in children with CP [ 10 – 15 ]. Even though preclinical research and early-phase clinical trial results are promising, the available data remains limited by small patient populations, inconsistent protocols, and a lack of long-term follow-up. There are currently no standardized recommendations for MSC source, dosage, delivery method, or patient selection [ 16 , 17 ]. Real-world data collected through structured case series is still valuable in this regard for documenting functional outcomes and directing future studies in regenerative therapy for CP. Four preschool children with spastic CP who underwent MSC therapy are presented in this case series study. Standardized tests of muscle strength, spasticity, and motor function were used to evaluate each case both before and after treatment in order to determine the therapeutic effects of MSC administration. Our goal is to add to the increasing amount of data demonstrating how regenerative therapies can help children with CP achieve better functional outcomes. 2. Materials and Methods 2.1. Study design This multicenter, open-label Phase I trial evaluated the safety and initial effectiveness of six triple-route administrations of umbilical cord (UC) derived MSCs. Eligible participants were four children (two girls and two boys), aged between 3 and 5 years, diagnosed with CP secondary to hypoxic ischemic encephalopathy (HIE) and/or intracranial hemorrhage, all of whom exhibited notable impairments and functional limitations (Table 1). Legal representatives of the patients provided written informed consent. The study received approval from the Turkish Ministry of Health, specifically the Department of Organ/Tissue Transplantation and Dialysis Services under the General Directorate of Health Services and its Scientific Committee (Approval Document Number: E-56733164-203-249680398, E-56733164-203-216374168, E-56733164-203-222165075, and E-56733164-203-228661723). 2.2. Umbilical Cord Collection, Processing and Quality Control UCs were collected from caesarean deliveries from multiple donors at LivMedCell Good Manufacturing Practice (GMP) facility in Istanbul, Turkey, following the acquisition of informed consent approved by the institutional regulatory board. All UCs were obtained postnatally from donors who had completed full-term pregnancies. The same donor cells were used in all applications. As previously described, the production and quality control testing of UC-MSCs were performed at LivMedCell GMP facility in Istanbul, Turkey [18]. In brief, UCs were rinsed with phosphate-buffered saline (Invitrogen/Gibco, Paisley, UK) to remove blood prior to dissection. The blood vessels were then removed, and the remaining tissue was cut into explants measuring 5-10 mm³. The explants were cultured using the explant method under humanized conditions (37 °C, 5% CO₂) until cell migration occurred. Once the cells reached 50-60% confluence, they were trypsinized, subcultured, and tested for quality control at passage 3. Quality control procedures were performed in accordance with standards from the EU Good Manufacturing Practice Guide (EudraLex, Vol. 4), Turkish Medicines and Medical Devices Agency, and the European Pharmacopoeia (Ph. Eur.). Processed UC-MSCs were cryopreserved and stored in a liquid nitrogen tank until thawed. After thawing, the cells were cultured and tested for characterization by gene expression profiling and flow cytometry; for sterility, using automated sterility testing system; for assessment of pyrogenicity; for determination of cell number and viability; and for tumorigenicity using a telomerase enzyme activity assay. The final UC-MSC preparations to be used for implantation for all four patients were prepared from passage 4 of cultures and suspended in serum physiologic at a final cell density of 1 × 10 6 MSCs/kg in 3 mL, 20 mL, and 30 mL for intrathecal (IT), intravenous (IV) and intramuscular (IM) administrations respectively. The final product was found to meet acceptance criteria and released with conforming final product forms (Supplementary Materials 1-4). 2.3. UC-MSC Administration and Associated Surgical Protocols Before initiating UC-MSC therapy, all patients underwent a comprehensive preoperative evaluation conducted by a multidisciplinary team comprising pediatric neurologists, neurosurgeons, anesthesiologists, and specialists in physical medicine and rehabilitation. These assessments were performed to exclude contraindications to sedoanalgesia or general anesthesia and to rule out systemic infections such as sepsis. The transplantation procedure was initiated only after confirmation of clinical stability. Allogeneic UC-MSCs were administered sequentially via IT, IM, and IV routes within an operating room environment. All patients subsequently received a total of six MSC therapy sessions, each administered at one-month intervals. IT administration was executed through lumbar puncture in accordance with established protocols from prior studies. IM delivery was performed under real-time ultrasound guidance to ensure precise localization of target muscle groups. IV infusion of UC-MSCs was carried out slowly over 30-minute duration to minimize potential hemodynamic fluctuations. Following the intervention, patients were initially monitored in the postoperative care unit. On the subsequent day, they were transferred to the Neurosurgery Department for continued clinical surveillance and initiation of a structured physical therapy and rehabilitation regimen. To mitigate physiological stress, no physical exercises were conducted on the days when UC-MSCs were administered. This standardized protocol was strictly followed across all administration sessions. 2.4. Therapeutic Assessment and Evaluation of Patients The safety profile for UC-MSC administration was defined by the absence of adverse clinical events such as infection, oncogenic transformation, neuropathic pain, or neurological deterioration throughout a 12-month follow-up period. In addition, patients were monitored for potential complications, including secondary infections, neuropathic pain, urinary tract infections, and pressure ulcers. Neurological assessments were conducted at baseline (before MSC therapy) and at final follow-up by a board-certified pediatric neurologist. To assess therapeutic efficacy clinical evaluations included standardized and validated tools to assess spasticity, motor function, trunk control, muscle strength, and joint mobility. The following outcome measures were applied: 2.4.1. Modified Ashworth Scale (MAS) for Spasticity MAS is a widely utilized clinical tool to assess muscle tone and resistance during passive movement, thus evaluating spasticity [19]. It enables individuals with CP to have semi-quantitative assessment of hypertonia. Each muscle group was scored on a 6-point scale: 0: No increase in muscle tone, 1: Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion (ROM), 1+: Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM, 2: More marked increase in muscle tone through most of the ROM, but affected part(s) easily moved, 4: Considerable increase in muscle tone, passive movement difficult, 5: Affected part(s) rigid in flexion or extension 2.4.2. Motricity Index for Motor Function Using task-specific scoring, the Motricity Index (MI)—which measures voluntary strength in certain muscle groups—evaluated motor performance [20]. Each action received an ordinal score ranging from 0 to 33; higher values indicate improved motor control and muscular strength. It included 10 tests involving pinch grip (test 1), elbow flexion, shoulder abduction, hip flexion, knee extension, ankle dorsiflexion (tests 2–6), rolling and transitions related to trunk control (test 7–10, used in conjunction with trunk control test). Scoring criteria for each test were; · Test 1: o 0: No movement o 11: Slight gripping movement observed o 19: Able to hold a cube but cannot overcome gravity o 22: Able to hold against gravity but weakly o 26: Resists external pull but is weaker than the opposite side o 33: Normal pinch strength · Tests 2–6: o 0: No movement o 9: No visible movement, but palpable contraction o 14: Partial movement, unable to complete full range or overcome gravity o 19: Completes full range of motion against gravity, no resistance o 25: Completes full range and resists some force, but weaker than contralateral side o 33: Normal strength · Tests 7–10: o 0: No movement o 9: Only contraction palpable o 14: Visible partial movement but cannot complete the task or overcome gravity To get overall limb and trunk scores, individual movement scores were summed up. Depending on the number of relevant examinations, each limb (upper or lower) had a maximum score of 99–100 points. Designed from clinical neurorehabilitation techniques in juvenile CP, this specific scoring system more precisely represents accurate patient outcome than binary instruments [20]. 2.4.3. Trunk Control Test (TCT) TCT was used to assess the patient's ability to control the trunk during four functional tasks; rolling to weak side, rolling to strong side, sitting up from lying down, balanced sitting on the bed. Each item was scored as; 0: unable, 12: able with some help and 25: able independently. Maximum possible score was 100. The TCT is considered a valid tool to predict mobility outcomes and assess axial control, especially in pediatric populations with spastic CP [21]. 2.4.4. Medical Research Council (MRC) Muscle Strength Scale Muscle strength was measured using the MRC grading system, which is a standard tool for evaluating voluntary muscle power [22]. Assessment was performed bilaterally on both distal and proximal muscles of upper and lower extremities following the grading system; Grade 0: No visible contraction, Grade 1: Flicker or trace of contraction, Grade 2: Active movement with gravity eliminated, Grade 3: Active movement against gravity, Grade 4: Active movement against gravity and some resistance, Grade 5: Normal power. 2.4.5. Joint Range of Motion Evaluation Using passive mobilization methods, joint mobility and range of motion were qualitatively assessed to find any pre- or post-treatment contractures or limitations. Data were recorded descriptively and then compared over sessions. 3. Case Presentations and Results Across all four patients, MSC therapy led to clinical improvements in spasticity (3/4), gross motor function (4/4), and muscle strength (4/4). Notably, all patients tolerated the six-session regimen without any AEs. While one patient showed unchanged spasticity scores, qualitative improvements in trunk control, postural stability, and emotional reactivity were observed. The combination of scale-based measures and caregiver feedback supports a positive therapeutic impact of MSC therapy in pediatric CP management. 3.1. Patient 1 The first patient (Pt1), born in August 2021, was diagnosed with HIE with spastic CP features. Her initial pediatric neurological evaluation was performed on March 2024, during which her muscle spasticity, gross motor functions and muscle strength were assessed. IM MSC administrations targeted the cervical, thoracic, and lumbar paraspinal muscles, as well as major motor groups including the extensors, quadriceps, tibialis anterior, deltoid, and external oblique abdominis muscles to target local spasticity and stimulate motor units (Table 1 ). A follow-up assessment in January 2025 was conducted using the same outcome measures. According to MAS, notable reductions in spasticity scores were observed, especially in the upper limbs and lower limb, reducing spasticity scores from 2 to 1 for her hands, knees, ankles and right elbow while her spasticity was reduced from + 1 to 1 for shoulder girdle and from 2 to 1 + for her left elbow (Fig. 1 B). Spasticity in the hip girdle remained unchanged. Gross motor function, evaluated via the MI and TCT, showed significant improvements, increasing her total arm score from 28 to 49, total leg score from 42 to 57 and trunk control measures such as rolling improved from 9 to 14, with sit-up capability improving from 0 to 14 (Fig. 1 A). In addition, muscle strength assessed by the MRC scale also improved markedly, with scores increasing from 3–4/5 to 5/5 across all tested muscle groups in both upper and lower extremities after 10 months of follow-up (Fig. 1 C). The treatment was well-tolerated without any adverse events (AEs) reported during or after the MSC therapy (Table 2 ). 3.2. Patient 2 The second patient (Pt2), born in May 2019, was diagnosed with mix type (spastic and Dyskinetic) CP and exhibited symptoms of spastic motor impairment. His initial clinical evaluation was conducted in 2023 during which spasticity, gross motor functions, and muscle strength were assessed using standardized outcome measures. IM injections targeted the cervical, thoracic, and lumbar paraspinal muscles, quadriceps, tibialis anterior, deltoid, hamstrings, brachialis, biceps, triceps, and hip adductors (Table 1 ). A follow-up evaluation in February 2024 demonstrated notable clinical improvements. According to the MAS, his spasticity scores improved significantly in multiple muscle groups: the shoulder girdle, elbows, and hands improving from grades 3–4 to 1 + bilaterally while his hip girdle spasticity improving from 2–4 to 1 bilaterally. However, his knee and ankle spasticity remained stable at grade 2 (Fig. 1 B). Remarkable improvements in gross motor functions were measured by the MI and TCT, increasing his total upper limb score from 38 to 55 and total lower limb score from 33 to 47. Grasping ability improved from 0 to 11 bilaterally, and flexion movements were enhanced. His trunk control improved from 0 to 9 in rolling ability, indicating better postural adjustments (Fig. 1 A). Muscle strength, evaluated by the MRC scale, improved from baseline scores of 3–4/5 to full strength (5/5) in both proximal and distal segments of the upper and lower limbs (Fig. 1 C). No range-of-motion limitations were observed before or after the therapy. There were no recorded AEs and the MSC therapy was well tolerated (Table 2 ). The patient showed improved head and trunk control, acquired the ability to roll and sit with support, became more emotionally expressive, and displayed cognitive gains including recognition and response to voices, according family reports and physician evaluations. Additionally, after the third application, it was determined during the examination that the patient's dystonia had disappeared and levels of secretion and respiratory problems reportedly decreased after therapy. 3.3. Patient 3 Born in July 2020, the third patient (Pt3) showed rather milder clinical symptoms than the other patients in this series after being diagnosed with spastic diplegic type of CP. His initial neurological evaluation was conducted in September 2024, and initial assessments revealed lower levels of spasticity and better preserved motor control compared to other patients in this study. Intramuscular applications for Pt3 targeted the paraspinal trunk extensors, hip extensors and abductors, quadriceps, tibialis anterior, deltoid, biceps, triceps, gluteus medius, and peroneal muscles (Table 1 ). Further gains were observed from the March 2025 follow-up evaluation after MSC therapy sessions. With scores ranging from grade 1 to 0 in the shoulder, elbow, and hand areas bilaterally, the MAS indicated that spasticity had totally resolved in all evaluated muscle groups (Fig. 1 B). Functional motor evaluations via MI and TCT revealed significant gains increasing upper limb score from 11 to 99 and lower limb score from 32 to 57. His elbow flexion and shoulder abduction were improved from 0 to 33 while his grasping increasing from 11 to 33. Additionally, his trunk control measures such as rolling improved from 9 to 14, and the patient gained the ability to move from supine to sitting (score improved from 0 to 14) (Fig. 1 A). Strength of muscles assessed on the MRC scale increased generally across all groups, increasing his lower limb scores from 3–4/5 to 5/5 in both distal and proximal segments and upper limb scores from 4–5/5 to 5/5 (Fig. 1 C). There were no ranges-of- motion restrictions pre- and post-treatment. There were no recorded AEs and MSC treatment was well tolerated (Table 2 ). Caregiver feedback and clinical observations indicate the patient developed better postural control and head stability, was able to roll in bed and lie prone, and show better cognitive interaction with parents. Emotional reactions improved, and after treatment complete resolution of secretion problems was recorded. Additionally, it was determined that the dystonia initially present in the patient's upper extremity disappeared after the second application. 3.4. Patient 4 The fourth patient (Pt4), born in November 2021, had global developmental delay and signs of spasticity following an intracranial hemorrhage. The patient's diagnosis was determined to be mixed-type CP, characterized by spastic diplegia and right-sided hemiparesis. Her first standardized clinical evaluation was done in December 2023 and included tests for spasticity, gross motor function, and muscle strength. The IM route was used to target key muscle groups including paraspinal extensors, quadriceps, tibialis anterior, deltoid, biceps, triceps, and the external oblique (Table 1 ). When her spasticity was reassessed in December 2024, there was no significant change observed according to the MAS. All measured areas, shoulders, elbows, hands, hips, knees, and ankles maintained their original scores between 1 and 2, showing no improvement in muscle tone (Fig. 1 B). However, she did improve in other ways. Her gross motor function remained stable, with already high MI scores staying consistent. Notably, her ability to shift from lying to sitting, which was absent before (score of 0), improved to a score of 14, suggesting a real gain in trunk stability and coordination (Fig. 1 A). Her muscle strength, which had already been quite good (between 4/5 and 5/5), improved further, reaching full strength (5/5) in both arms and legs by the final follow-up (Fig. 1 C). No range-of-motion limitations were noted either before or after therapy (Table 2 ). Beyond these scores, her family and clinicians noted clear improvements in day-to-day function. She became more responsive to verbal commands, began producing intentional sounds, and gained better head and body control. She also started to recognize voices and interact more emotionally. Crawling posture became possible, and there was a clear drop in secretions and respiratory issues. Overall, the therapy was well-tolerated, with no AEs reported. Table 1 Baseline Demographics and Clinical Characteristics of the Four Pediatric Patients with Spastic CP Patient ID Gender Birth Date Diagnosis / Cause Initial Evaluation Follow-up Date MSC Doses Routes of Administration Targeted Muscles (IM injections) Pt1 F Aug 2021 CP (Spastic, HIE) Mar 2024 Jan 2025 6 sessions IV + IT + IM Paraspinals, Quadriceps, Tibialis Ant., Deltoid, Ext. Oblique Pt2 M May 2019 CP (Spastic and dyskinetic) 2023 Feb 2024 6 sessions IV + IT + IM Paraspinals, Quadriceps, Tibialis Ant., Deltoid, Biceps, Triceps, Hip Adductors Pt3 M Jul 2020 CP (Spastic diplegic type, mild symptoms) Sep 2024 Mar 2025 6 sessions IV + IT + IM Paraspinals, Hip Ext/Abd, Quadriceps, Deltoid, Gluteus Medius, Peroneals Pt4 F Nov 2021 CP (Mixed type, Intracranial Hemorrhage) Dec 2023 Dec 2024 6 sessions IV + IT + IM Paraspinals, Quadriceps, Tibialis Ant., Deltoid, Biceps, Triceps, Ext. Oblique Table 2 Pre- and Post-Treatment Clinical Outcomes Following UC-MSC Therapy in Pediatric CP Patients. Patient ID MAS (Pre) MAS (Post) MI Arm (Pre→Post) MI Leg (Pre→Post) TCT (Pre→Post) MRC (Pre→Post) Qualitative Gains Pt1 2 (hands, knees, elbows) 1 (hands, knees, elbows) 28 → 49 42 → 57 Sit-up: 0→14 3–4/5 → 5/5 Better posture, motor control, full limb power. Pt2 3–4 (upper and lower limbs) 1 + to 1 (upper limbs/hip) 38 → 55 33 → 47 Roll: 0→9 3–4/5 → 5/5 Gains in cognition, emotion, and motor control. Patient’s dystonia disappeared. Pt3 1 (upper limbs) 0 (all limbs) 11 → 99 32 → 57 Sit-up: 0→14 3–4/5 → 5/5 Improved postural control, emotional interaction. Patient’s upper limb dystonia disappeared Pt4 1–2 (all limbs) No change High → High High → High Sit-up: 0→14 4–5/5 → 5/5 Head control, vocalization, crawling posture. 4. Discussion The present case series demonstrates that children with spastic CP can clinically significantly benefit from UC-MSC treatment. Improvements in at least one of the assessed domains—spasticity, muscle strength, motor function, trunk control, and daily functional interaction—were observed among all four patients at the end of 10–12 months follow-up period. Significantly, no adverse outcomes were observed during the six-session treatment course, supporting the safety of the cell therapy which is in parallel with previous studies on MSC use in pediatric populations. Patients 1 to 3 showed reductions in spasticity identified by the MAS, with muscle tone scores falling by 1–2 points across groups of upper and lower limbs. Particularly patient 3 showed total spasticity recovery. The disappearance of the pronounced dystonias observed in the neurological examinations of Pt2 and Pt3 prior to stem cell treatment in the second and third applications can be explained by the variability of the patients' anti-inflammatory responses. Across the cohort, there were notable increases in gross motor function measured using the MI and TCT. Especially, sit-to- stand transition and trunk coordination which are two important markers of central motor control, improved in patients 1, 2, and 4, supporting the suggestion that MSCs may enhance neural circuit plasticity [ 23 , 24 ]. In MRC scale evaluations, all four patients demonstrated improvements in muscle strength; at follow-up, they achieved either near or full grade 5 strength. Patient 4 showed improved head and postural control even though her MAS scores did not change from lying to sitting. This draws attention to a possible dissociation between spasticity reduction and functional recovery, a finding consistent with previous studies implying that MSCs may have neuromodulating properties beyond solely tone management [ 25 , 26 ]. This study has several limitations that should be acknowledged. Firstly, the small sample size reduces the generalizability of the outcomes and makes it difficult to separate treatment effects from normal developmental progression without having a comparison group. The individualized nature of functional improvements also introduces variability that may not be fully captured by standardized scoring systems. Furthermore, even if caregiver-reported outcomes provide insightful analysis of qualitative changes, they are still subjective and would benefit from further validation via blinded assessments. An additional crucial factor is the financial obstacle related to cell therapies. Cell-based advanced therapy medicinal products' expensive manufacturing and clinical application costs not only limit their general accessibility but also could explain the limited cohorts in many of such trials. Expanding access depends on addressing cost-related issues, particularly in countries with low or middle incomes where the burden of CP remains disproportionately high. Comprehensive evaluation of the therapeutic potential and scalability of MSC treatment for CP requires longer-term follow-up research with larger, randomized cohorts and cost-effective analyses. 5. Conclusion This case series adds to the accumulating data supporting the safety and potential efficacy of UC-MSC therapy for pediatric patients with spastic CP. Each patient in this small cohort demonstrated substantial improvements in muscle tone, strength, mobility, or daily interactions, highlighting how cell therapies may give hope to families navigating the difficulties of CP. Although the outcomes were optimistic, particularly in terms of functional gains and quality of life enhancements, it is important to acknowledge variations between individuals in response. One contributing factor to the small cohort size in such clinical studies is the high cost of cell-based advanced therapeutical medicinal products, which limits broader accessibility. Reducing the manufacturing costs and making these treatments more accessible could offer renewed hope to children and families affected by CP worldwide, particularly in resource-limited settings. Results of this study highlight the need of more extensive and controlled clinical studies to accurately define the therapeutic potential of MSCs and direct their future application in pediatric neurorehabilitation. Declarations Ethics approval: Mesenchymal stem cell products were obtained from the LivMedCell Good Manufacturing Practice (GMP) facility located in Istanbul, Turkey. The umbilical cord was acquired from multiple donors after obtaining their informed consent, in accordance with the authorization of the institutional regulatory board. All cell therapy applications were performed following informed consent of the patient. Clinical trial number: Not applicable (Clinical applications in this study were approved by the Turkish Ministry of Health, the Department of Organ/Tissue Transplantation and Dialysis Services under the General Directorate of Health Services and its Scientific Committee (Approval Document Number: E-56733164-203-249680398, E-56733164-203-216374168, E-56733164-203-222165075, and E-56733164-203-228661723). Consent to participate: All authors confirm their full participation in the preparation and submission of the manuscript titled “Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy" to the Stem Cell Reviews and Reports Journal. All authors have contributed intellectually to the manuscript, reviewed its content, and consented to its submission. The corresponding author (Ayberk Akat, Ph.D.) is authorized to communicate with the journal on behalf of all authors. Consent for publication: All authors approve the final version of the manuscript for publication. They consent to the publication of relevant personal information (such as name, affiliation) in accordance with journal policies. Availability of data and material: The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions: GK: Comprehensive evaluation of patients, analysis of test results, performed neurological examinations, applied cell therapies, and conducted follow-ups to monitor the patients’ progress. Her expertise and dedication were pivotal in managing the patients care throughout the treatment period. AA: Quality control analysis of cell therapy products applied to the patients, collected data, analyzed results, and drafted the article. ONÖ: Responsible for production of clinical grade cell therapy products applied to the patients, collected data, analyzed results, and drafted the article. ÇÖ: Evaluation of patients, application of cell therapy products, and conducted follow-ups to monitor the patients’ progress. MC: Physical therapy, rehabilitation and evaluation of the patients, conducted follow-ups to monitor the patients’ progress. EK: Study conception and design, responsible for the production of cell therapy products, revised the article critically for important intellectual content. Acknowledgements: Not applicable. References Vitrikas K, Dalton H, Breish D (2020) Cerebral Palsy: An Overview. Am Family Phys 101(4):213–220 McIntyre S, Goldsmith S, Webb A, Ehlinger V, Hollung SJ, McConnell K, Arnaud C, Smithers-Sheedy H, Oskoui M, Khandaker G, Himmelmann K, Global CP, Prevalence Group (2022) Global prevalence of cerebral palsy: A systematic analysis. Dev Med Child Neurol 64(12):1494–1506. https://doi.org/10.1111/dmcn.15346 Delobel-Ayoub M, Ehlinger V, Klapouszczak D, Troha Gergeli A, Sellier E, Hollody K, Virella D, Vik T, Perret C, Vidart d'Egurbide Bagazgoïtia, Horridge N, K., Arnaud C (2025) Postneonatal Cerebral Palsy in Europe: Prevalence and Clinical Characteristics According to Contributory Events: An SCPE Study. Pediatric and perinatal epidemiology, 39(3), 287–298. https://doi.org/10.1111/ppe.13164 Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, Dan B, Jacobsson B (2007) A report: the definition and classification of cerebral palsy April 2006. Supplement 109:8–14Developmental medicine and child neurology McCoy SW, Palisano R, Avery L, Jeffries L, Laforme Fiss A, Chiarello L, Hanna S (2020) Physical, occupational, and speech therapy for children with cerebral palsy. Dev Med Child Neurol 62(1):140–146. https://doi.org/10.1111/dmcn.14325 Reilly M, Liuzzo K, Blackmer AB (2020) Pharmacological Management of Spasticity in Children with Cerebral Palsy. J Pediatr health care: official publication Natl Association Pediatr Nurse Associates Practitioners 34(5):495–509. https://doi.org/10.1016/j.pedhc.2020.04.010 Stasolla F, Caffò AO, Perilli V, Boccasini A, Damiani R, D'Amico F (2019) Assistive technology for promoting adaptive skills of children with cerebral palsy: ten cases evaluation. Disabil Rehabil Assist Technol 14(5):489–502. https://doi.org/10.1080/17483107.2018.1467972 Duc Lien N, Van Linh N, Van C, Giang NT, King LT, Tarren DT, Dat A, N. D., Rocque BG (2024) Selective Dorsal Rhizotomy for Spastic Cerebral Palsy: Report of 18 Cases Performed in the North of Vietnam. World Neurosurg 188:e128–e133. https://doi.org/10.1016/j.wneu.2024.05.055 Theroux MC, DiCindio S (2014) Major surgical procedures in children with cerebral palsy. Anesthesiol Clin 32(1):63–81. https://doi.org/10.1016/j.anclin.2013.10.014 Akat A, Karaöz E (2025) A systematic review of cell therapy modalities and outcomes in cerebral palsy. Mol Cell Biochem 480(2):891–922. https://doi.org/10.1007/s11010-024-05072-3 Gu J, Huang L, Zhang C et al (2020) Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial. Stem Cell Res Ther 11:43. https://doi.org/10.1186/s13287-019-1545-x Vankeshwaram V, Maheshwary A, Mohite D, Omole JA, Khan S (2020) Is Stem Cell Therapy the New Savior for Cerebral Palsy Patients? Rev Cureus 12(9):e10214. https://doi.org/10.7759/cureus.10214 Chen W, Ren Q, Zhou J, Liu W (2024) Mesenchymal Stem Cell-Induced Neuroprotection in Pediatric Neurological Diseases: Recent Update of Underlying Mechanisms and Clinical Utility. Appl Biochem Biotechnol 196(9):5843–5858. https://doi.org/10.1007/s12010-023-04752-y Amanat M, Majmaa A, Zarrabi M et al (2021) Clinical and imaging outcomes after intrathecal injection of umbilical cord tissue mesenchymal stem cells in cerebral palsy: a randomized double-blind sham-controlled clinical trial. Stem Cell Res Ther 12:439. https://doi.org/10.1186/s13287-021-02513-4 Akhlaghpasand M, Hosseinpou M, Hajikarimloo B, Hajirajizadeh A, Golmohammadi M, Tavaneei R, Mohammad1 I, Angoharibari NA, MohammadEbrahim N, Zali A, Oraee-Yazdani S (2025) Repeated intrathecal injections of autologous bone marrow-derived mesenchymal stem cells for spastic cerebral palsy: Single-arm safety and preliminary efficacy clinical trial. Journal of Neurorestoratology, 2025, 100207. https://doi.org/10.1016/j.jnrt.2025.100207 Finch-Edmondson M, Paton MCB, Honan I, Karlsson P, Stephenson C, Chiu D, Reedman S, Griffin AR, Morgan C, Novak I (2022) Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy. J Clin Med 11(24):7319. https://doi.org/10.3390/jcm11247319 Qu J, Zhou L, Zhang H, Han D, Luo Y, Chen J, Li L, Zou Z, He Z, Zhang M, Ye J (2022) Efficacy and safety of stem cell therapy in cerebral palsy: A systematic review and meta-analysis. Front Bioeng Biotechnol 10:1006845. https://doi.org/10.3389/fbioe.2022.1006845 Hüzmeli H, Akat A, Özkara A, Ceylan E, Özenç E, Karaöz E (2025) Extracellular Vesicle-Enhanced Stem Cell Therapy in Acute Myocardial Infarction: A Case Report of Cardiac Regeneration from a Bypass Surgery. Stem Cell Rev Rep. https://doi.org/10.1007/s12015-025-10910-y Bohannon RW, Smith MB (1987) Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 67(2):206–207. https://doi.org/10.1093/ptj/67.2.206 Demeurisse G, Demol O, Robaye E (1980) Motor evaluation in vascular hemiplegia. Eur Neurol 19(6):382–389. https://doi.org/10.1159/000115178 Franchignoni FP, Tesio L, Ricupero C, Martino MT (1997) Trunk control test as an early predictor of stroke rehabilitation outcome. Stroke 28(7):1382–1385. https://doi.org/10.1161/01.str.28.7.1382 Medical Research Council (1976) Aids to the examination of the peripheral nervous system (Memorandum No. 45). Her Majesty's Stationery Office Zhang X, Kuang Q, Xu J, Lin Q, Chi H, Yu D (2024) MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research. Biomolecules 14(5):538. https://doi.org/10.3390/biom14050538 Li M, Chen H, Zhu M (2022) Mesenchymal stem cells for regenerative medicine in central nervous system. Front Neurosci 16:1068114. https://doi.org/10.3389/fnins.2022.1068114 Seo JH, Cho SR (2012) Neurorestoration induced by mesenchymal stem cells: potential therapeutic mechanisms for clinical trials. Yonsei Med J 53(6):1059–1067. https://doi.org/10.3349/ymj.2012.53.6.1059 Huang P, Gebhart N, Richelson E, Brott TG, Meschia JF, Zubair AC (2014) Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation. Cytotherapy 16(10):1336–1344. https://doi.org/10.1016/j.jcyt.2014.05.007 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7202210","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":511529311,"identity":"b1b11adb-964c-4138-8e05-91e2fb5b5327","order_by":0,"name":"Gülşen Köse","email":"","orcid":"","institution":"Istinye University","correspondingAuthor":false,"prefix":"","firstName":"Gülşen","middleName":"","lastName":"Köse","suffix":""},{"id":511529312,"identity":"55c5ccf5-df30-498f-b93b-676245a2d4b1","order_by":1,"name":"Ayberk Akat","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDACHjB5AMhgBhIMEjLEaGFsgGhhSwBp4SFFC48BwlZ8gL/n8PMHP9vuyJn3nPn86kaNBQ8D++GjG/BpkTjbZtjY2/bMWOZs7zbrnGNAh/Gkpd3Aa815BsMG3rbDiTP4ebcZ57ABtUjwmOHVIn+e/WPj37bD9TP4eZ4Z5/wjQovB2R7DZqAtCRK8PcyPc9uI0GJ45kzhbJlzzwxn8BwzY87tk+BhI+QXuTPpGz6+KbsjL8GT/Phzzrc6OX72w8fwex8EGNnAFJsEmCSoHAz+gEnmD8SpHgWjYBSMgpEGACajS5sG6uYZAAAAAElFTkSuQmCC","orcid":"","institution":"Girne American University","correspondingAuthor":true,"prefix":"","firstName":"Ayberk","middleName":"","lastName":"Akat","suffix":""},{"id":511529313,"identity":"84df972f-9106-441f-a4b7-38e3f783e1ec","order_by":2,"name":"Olga Nehir Öztel","email":"","orcid":"","institution":"Liv Hospital","correspondingAuthor":false,"prefix":"","firstName":"Olga","middleName":"Nehir","lastName":"Öztel","suffix":""},{"id":511529314,"identity":"bb9530c9-6b71-4a51-be30-315a234ffe69","order_by":3,"name":"Çağatay Öztürk","email":"","orcid":"","institution":"Liv Hospital","correspondingAuthor":false,"prefix":"","firstName":"Çağatay","middleName":"","lastName":"Öztürk","suffix":""},{"id":511529315,"identity":"a81ba707-0fc1-4bb9-8919-574b328e6818","order_by":4,"name":"Merve Cemil","email":"","orcid":"","institution":"Liv Hospital","correspondingAuthor":false,"prefix":"","firstName":"Merve","middleName":"","lastName":"Cemil","suffix":""},{"id":511529316,"identity":"56505f19-2a8d-402c-9b36-1444c16a9a36","order_by":5,"name":"Erdal Karaöz","email":"","orcid":"","institution":"Istinye University","correspondingAuthor":false,"prefix":"","firstName":"Erdal","middleName":"","lastName":"Karaöz","suffix":""}],"badges":[],"createdAt":"2025-07-24 06:38:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7202210/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7202210/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91305625,"identity":"91a8f598-899e-4973-9a4b-6239851b1f2d","added_by":"auto","created_at":"2025-09-15 06:27:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137865,"visible":true,"origin":"","legend":"\u003cp\u003ePre- and post-treatment clinical evaluation results of four CP patients using the Motricity Index and Trunk Control Test (A), Modified Ashworth Scale (B), and MRC Muscle Strength Scale (C). Improvements in motor function, trunk control, and muscle strength, along with reductions in spasticity, were observed in several patients following MSC therapy.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7202210/v1/947a4f7ab547aca62a124d2a.png"},{"id":92837657,"identity":"30d137b5-d06c-48f0-a5b4-db8f819ad8ab","added_by":"auto","created_at":"2025-10-06 08:09:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":798782,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7202210/v1/8fc68169-69ce-45ca-ac73-e81850dc774a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCerebral palsy (CP) represents a group of permanent, non-progressive neurological disorders that affect movement, muscle tone, and posture, resulting from damage to the developing brain, most commonly before or during birth [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Recent epidemiological studies have given revised understanding of the worldwide CP prevalence. Reflecting improvements in perinatal and neonatal care, it has been revealed that the birth prevalence of CP in high-income countries has dropped to almost 1.6 per 1,000 live births, while low and middle-income countries show a higher frequency; estimates range from 3.4 per 1,000 live births, underscoring disparities in healthcare access and quality [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Though non-progressive, the clinical symptoms of CP sometimes cause gradual musculoskeletal problems that over time greatly affect functional independence and quality of life. Often resulting in joint contractures and gait abnormalities, spastic CP is the most common type and is defined by increased muscle tone, exaggerated reflexes, and impaired voluntary movement [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. CP is a disorder that should be managed through a multidisciplinary approach aimed at improving motor function, reducing complications, and enhancing quality of life. Conventional interventions include physical and occupational therapy to enhance mobility and daily functioning, speech therapy for communication difficulties, and medications such as baclofen or botulinum toxin to manage spasticity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. To treat severe muscle tightness or skeletal abnormalities, orthopedic surgeries or selective dorsal rhizotomy may be used [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, these treatments do not address the underlying neurological damage; instead, they mainly provide symptomatic relief. Mesenchymal stem cell (MSC) therapy is one of the emerging treatments being investigated for its potential for addressing neural injury and enhancing motor outcomes in patients with CP [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDue to their numerous regenerative attributes, MSCs have become an appealing therapy option for CP. MSCs have potent immunomodulatory and anti-inflammatory properties that may reduce the neuroinflammation associated with CP. Furthermore, MSCs secrete neurotrophic factors that facilitate neural repair and functional recovery by enhancing synaptic plasticity, promoting neurogenesis, and supporting neuronal survival [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Clinical evidence has shown that MSC therapy has an impressive safety record and can significantly improve gross motor function and overall neurological outcomes in children with CP [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Even though preclinical research and early-phase clinical trial results are promising, the available data remains limited by small patient populations, inconsistent protocols, and a lack of long-term follow-up. There are currently no standardized recommendations for MSC source, dosage, delivery method, or patient selection [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Real-world data collected through structured case series is still valuable in this regard for documenting functional outcomes and directing future studies in regenerative therapy for CP.\u003c/p\u003e\u003cp\u003eFour preschool children with spastic CP who underwent MSC therapy are presented in this case series study. Standardized tests of muscle strength, spasticity, and motor function were used to evaluate each case both before and after treatment in order to determine the therapeutic effects of MSC administration. Our goal is to add to the increasing amount of data demonstrating how regenerative therapies can help children with CP achieve better functional outcomes.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1.\u0026nbsp; \u0026nbsp;Study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter, open-label Phase I trial evaluated the safety and initial effectiveness of six triple-route administrations of umbilical cord (UC) derived MSCs. Eligible participants were four children (two girls and two boys), aged between 3 and 5 years, diagnosed with CP secondary to hypoxic ischemic encephalopathy (HIE) and/or intracranial hemorrhage, all of whom exhibited notable impairments and functional limitations (Table 1). Legal representatives of the patients provided written informed consent. The study received approval from the Turkish Ministry of Health, specifically the Department of Organ/Tissue Transplantation and Dialysis Services under the General Directorate of Health Services and its Scientific Committee (Approval Document Number: E-56733164-203-249680398, E-56733164-203-216374168, E-56733164-203-222165075, and E-56733164-203-228661723).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.\u0026nbsp; \u0026nbsp;Umbilical Cord Collection, Processing and Quality Control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUCs were collected from caesarean deliveries from multiple donors at LivMedCell Good Manufacturing Practice (GMP) facility in Istanbul, Turkey, following the acquisition of informed consent approved by the institutional regulatory board. All UCs were obtained postnatally from donors who had completed full-term pregnancies. The same donor cells were used in all applications.\u003c/p\u003e\n\u003cp\u003eAs previously described, the production and quality control testing of UC-MSCs were performed at LivMedCell GMP facility in Istanbul, Turkey [18]. In brief, UCs were rinsed with phosphate-buffered saline (Invitrogen/Gibco, Paisley, UK) to remove blood prior to dissection. The blood vessels were then removed, and the remaining tissue was cut into explants measuring 5-10 mm\u0026sup3;. The explants were cultured using the explant method under humanized conditions (37 \u0026deg;C, 5% CO₂) until cell migration occurred. Once the cells reached 50-60% confluence, they were trypsinized, subcultured, and tested for quality control at passage 3. Quality control procedures were performed in accordance with standards from the EU Good Manufacturing Practice Guide (EudraLex, Vol. 4), Turkish Medicines and Medical Devices Agency, and the European Pharmacopoeia (Ph. Eur.). Processed UC-MSCs were cryopreserved and stored in a liquid nitrogen tank until thawed. After thawing, the cells were cultured and tested for characterization by gene expression profiling and flow cytometry; for sterility, using automated sterility testing system; for assessment of pyrogenicity; for determination of cell number and viability; and for tumorigenicity using a telomerase enzyme activity assay. The final UC-MSC preparations to be used for implantation for all four patients were prepared from passage 4 of cultures and suspended in serum physiologic at a final cell density of 1 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e MSCs/kg in 3 mL, 20 mL, and 30 mL for intrathecal (IT), intravenous (IV) and intramuscular (IM) administrations respectively. The final product was found to meet acceptance criteria and released with conforming final product forms (Supplementary Materials 1-4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3.\u0026nbsp; \u0026nbsp;UC-MSC Administration and Associated Surgical Protocols\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore initiating UC-MSC therapy, all patients underwent a comprehensive preoperative evaluation conducted by a multidisciplinary team comprising pediatric neurologists, neurosurgeons, anesthesiologists, and specialists in physical medicine and rehabilitation. These assessments were performed to exclude contraindications to sedoanalgesia or general anesthesia and to rule out systemic infections such as sepsis. The transplantation procedure was initiated only after confirmation of clinical stability.\u003c/p\u003e\n\u003cp\u003eAllogeneic UC-MSCs were administered sequentially via IT, IM, and IV routes within an operating room environment. All patients subsequently received a total of six MSC therapy sessions, each administered at one-month intervals. IT administration was executed through lumbar puncture in accordance with established protocols from prior studies. IM delivery was performed under real-time ultrasound guidance to ensure precise localization of target muscle groups. IV infusion of UC-MSCs was carried out slowly over 30-minute duration to minimize potential hemodynamic fluctuations.\u003c/p\u003e\n\u003cp\u003eFollowing the intervention, patients were initially monitored in the postoperative care unit. On the subsequent day, they were transferred to the Neurosurgery Department for continued clinical surveillance and initiation of a structured physical therapy and rehabilitation regimen. To mitigate physiological stress, no physical exercises were conducted on the days when UC-MSCs were administered. This standardized protocol was strictly followed across all administration sessions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.\u0026nbsp; \u0026nbsp;Therapeutic Assessment and Evaluation of Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe safety profile for UC-MSC administration was defined by the absence of adverse clinical events such as infection, oncogenic transformation, neuropathic pain, or neurological deterioration throughout a 12-month follow-up period. In addition, patients were monitored for potential complications, including secondary infections, neuropathic pain, urinary tract infections, and pressure ulcers.\u003c/p\u003e\n\u003cp\u003eNeurological assessments were conducted at baseline (before MSC therapy) and at final follow-up by a board-certified pediatric neurologist. To assess therapeutic efficacy clinical evaluations included standardized and validated tools to assess spasticity, motor function, trunk control, muscle strength, and joint mobility. The following outcome measures were applied:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.1.\u0026nbsp;Modified Ashworth Scale (MAS) for Spasticity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMAS is a widely utilized clinical tool to assess muscle tone and resistance during passive movement, thus evaluating spasticity [19]. It enables individuals with CP to have semi-quantitative assessment of hypertonia. Each muscle group was scored on a 6-point scale:\u003c/p\u003e\n\u003cp\u003e0: No increase in muscle tone, 1: Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion (ROM), 1+: Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM, 2: More marked increase in muscle tone through most of the ROM, but affected part(s) easily moved, 4: Considerable increase in muscle tone, passive movement difficult, 5: Affected part(s) rigid in flexion or extension\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.2.\u0026nbsp;Motricity Index for Motor Function\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing task-specific scoring, the Motricity Index (MI)\u0026mdash;which measures voluntary strength in certain muscle groups\u0026mdash;evaluated motor performance [20]. Each action received an ordinal score ranging from 0 to 33; higher values indicate improved motor control and muscular strength. It included 10 tests involving pinch grip (test 1), elbow flexion, shoulder abduction, hip flexion, knee extension, ankle dorsiflexion (tests 2\u0026ndash;6), rolling and transitions related to trunk control (test 7\u0026ndash;10, used in conjunction with trunk control test). Scoring criteria for each test were;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026middot; Test 1:\u003c/p\u003e\n\u003cp\u003eo 0: No movement\u003c/p\u003e\n\u003cp\u003eo 11: Slight gripping movement observed\u003c/p\u003e\n\u003cp\u003eo 19: Able to hold a cube but cannot overcome gravity\u003c/p\u003e\n\u003cp\u003eo 22: Able to hold against gravity but weakly\u003c/p\u003e\n\u003cp\u003eo 26: Resists external pull but is weaker than the opposite side\u003c/p\u003e\n\u003cp\u003eo 33: Normal pinch strength\u003c/p\u003e\n\u003cp\u003e\u0026middot; Tests 2\u0026ndash;6:\u003c/p\u003e\n\u003cp\u003eo 0: No movement\u003c/p\u003e\n\u003cp\u003eo 9: No visible movement, but palpable contraction\u003c/p\u003e\n\u003cp\u003eo 14: Partial movement, unable to complete full range or overcome gravity\u003c/p\u003e\n\u003cp\u003eo 19: Completes full range of motion against gravity, no resistance\u003c/p\u003e\n\u003cp\u003eo 25: Completes full range and resists some force, but weaker than contralateral side\u003c/p\u003e\n\u003cp\u003eo 33: Normal strength\u003c/p\u003e\n\u003cp\u003e\u0026middot; Tests 7\u0026ndash;10:\u003c/p\u003e\n\u003cp\u003eo 0: No movement\u003c/p\u003e\n\u003cp\u003eo 9: Only contraction palpable\u003c/p\u003e\n\u003cp\u003eo 14: Visible partial movement but cannot complete the task or overcome gravity\u003c/p\u003e\n\u003cp\u003eTo get overall limb and trunk scores, individual movement scores were summed up. Depending on the number of relevant examinations, each limb (upper or lower) had a maximum score of 99\u0026ndash;100 points. Designed from clinical neurorehabilitation techniques in juvenile CP, this specific scoring system more precisely represents accurate patient outcome than binary instruments [20].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.3.\u0026nbsp;Trunk Control Test (TCT)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTCT was used to assess the patient\u0026apos;s ability to control the trunk during four functional tasks; rolling to weak side, rolling to strong side, sitting up from lying down, balanced sitting on the bed. Each item was scored as; 0: unable, 12: able with some help and 25: able independently. Maximum possible score was 100. The TCT is considered a valid tool to predict mobility outcomes and assess axial control, especially in pediatric populations with spastic CP [21].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.4.\u0026nbsp;Medical Research Council (MRC) Muscle Strength Scale\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMuscle strength was measured using the MRC grading system, which is a standard tool for evaluating voluntary muscle power [22]. Assessment was performed bilaterally on both distal and proximal muscles of upper and lower extremities following the grading system; Grade 0: No visible contraction, Grade 1: Flicker or trace of contraction, Grade 2: Active movement with gravity eliminated, Grade 3: Active movement against gravity, Grade 4: Active movement against gravity and some resistance, Grade 5: Normal power.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.5.\u0026nbsp;Joint Range of Motion Evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing passive mobilization methods, joint mobility and range of motion were qualitatively assessed to find any pre- or post-treatment contractures or limitations. Data were recorded descriptively and then compared over sessions.\u003c/p\u003e"},{"header":"3. Case Presentations and Results","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAcross all four patients, MSC therapy led to clinical improvements in spasticity (3/4), gross motor function (4/4), and muscle strength (4/4). Notably, all patients tolerated the six-session regimen without any AEs. While one patient showed unchanged spasticity scores, qualitative improvements in trunk control, postural stability, and emotional reactivity were observed. The combination of scale-based measures and caregiver feedback supports a positive therapeutic impact of MSC therapy in pediatric CP management.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Patient 1\u003c/h2\u003e\u003cp\u003eThe first patient (Pt1), born in August 2021, was diagnosed with HIE with spastic CP features. Her initial pediatric neurological evaluation was performed on March 2024, during which her muscle spasticity, gross motor functions and muscle strength were assessed. IM MSC administrations targeted the cervical, thoracic, and lumbar paraspinal muscles, as well as major motor groups including the extensors, quadriceps, tibialis anterior, deltoid, and external oblique abdominis muscles to target local spasticity and stimulate motor units (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A follow-up assessment in January 2025 was conducted using the same outcome measures. According to MAS, notable reductions in spasticity scores were observed, especially in the upper limbs and lower limb, reducing spasticity scores from 2 to 1 for her hands, knees, ankles and right elbow while her spasticity was reduced from +\u0026thinsp;1 to 1 for shoulder girdle and from 2 to 1\u0026thinsp;+\u0026thinsp;for her left elbow (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Spasticity in the hip girdle remained unchanged. Gross motor function, evaluated via the MI and TCT, showed significant improvements, increasing her total arm score from 28 to 49, total leg score from 42 to 57 and trunk control measures such as rolling improved from 9 to 14, with sit-up capability improving from 0 to 14 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). In addition, muscle strength assessed by the MRC scale also improved markedly, with scores increasing from 3\u0026ndash;4/5 to 5/5 across all tested muscle groups in both upper and lower extremities after 10 months of follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). The treatment was well-tolerated without any adverse events (AEs) reported during or after the MSC therapy (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Patient 2\u003c/h2\u003e\u003cp\u003eThe second patient (Pt2), born in May 2019, was diagnosed with mix type (spastic and Dyskinetic) CP and exhibited symptoms of spastic motor impairment. His initial clinical evaluation was conducted in 2023 during which spasticity, gross motor functions, and muscle strength were assessed using standardized outcome measures. IM injections targeted the cervical, thoracic, and lumbar paraspinal muscles, quadriceps, tibialis anterior, deltoid, hamstrings, brachialis, biceps, triceps, and hip adductors (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA follow-up evaluation in February 2024 demonstrated notable clinical improvements. According to the MAS, his spasticity scores improved significantly in multiple muscle groups: the shoulder girdle, elbows, and hands improving from grades 3\u0026ndash;4 to 1\u0026thinsp;+\u0026thinsp;bilaterally while his hip girdle spasticity improving from 2\u0026ndash;4 to 1 bilaterally. However, his knee and ankle spasticity remained stable at grade 2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Remarkable improvements in gross motor functions were measured by the MI and TCT, increasing his total upper limb score from 38 to 55 and total lower limb score from 33 to 47. Grasping ability improved from 0 to 11 bilaterally, and flexion movements were enhanced. His trunk control improved from 0 to 9 in rolling ability, indicating better postural adjustments (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Muscle strength, evaluated by the MRC scale, improved from baseline scores of 3\u0026ndash;4/5 to full strength (5/5) in both proximal and distal segments of the upper and lower limbs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). No range-of-motion limitations were observed before or after the therapy. There were no recorded AEs and the MSC therapy was well tolerated (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The patient showed improved head and trunk control, acquired the ability to roll and sit with support, became more emotionally expressive, and displayed cognitive gains including recognition and response to voices, according family reports and physician evaluations. Additionally, after the third application, it was determined during the examination that the patient's dystonia had disappeared and levels of secretion and respiratory problems reportedly decreased after therapy.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Patient 3\u003c/h2\u003e\u003cp\u003eBorn in July 2020, the third patient (Pt3) showed rather milder clinical symptoms than the other patients in this series after being diagnosed with spastic diplegic type of CP. His initial neurological evaluation was conducted in September 2024, and initial assessments revealed lower levels of spasticity and better preserved motor control compared to other patients in this study.\u003c/p\u003e\u003cp\u003eIntramuscular applications for Pt3 targeted the paraspinal trunk extensors, hip extensors and abductors, quadriceps, tibialis anterior, deltoid, biceps, triceps, gluteus medius, and peroneal muscles (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Further gains were observed from the March 2025 follow-up evaluation after MSC therapy sessions. With scores ranging from grade 1 to 0 in the shoulder, elbow, and hand areas bilaterally, the MAS indicated that spasticity had totally resolved in all evaluated muscle groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Functional motor evaluations via MI and TCT revealed significant gains increasing upper limb score from 11 to 99 and lower limb score from 32 to 57. His elbow flexion and shoulder abduction were improved from 0 to 33 while his grasping increasing from 11 to 33. Additionally, his trunk control measures such as rolling improved from 9 to 14, and the patient gained the ability to move from supine to sitting (score improved from 0 to 14) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Strength of muscles assessed on the MRC scale increased generally across all groups, increasing his lower limb scores from 3\u0026ndash;4/5 to 5/5 in both distal and proximal segments and upper limb scores from 4\u0026ndash;5/5 to 5/5 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). There were no ranges-of- motion restrictions pre- and post-treatment. There were no recorded AEs and MSC treatment was well tolerated (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCaregiver feedback and clinical observations indicate the patient developed better postural control and head stability, was able to roll in bed and lie prone, and show better cognitive interaction with parents. Emotional reactions improved, and after treatment complete resolution of secretion problems was recorded. Additionally, it was determined that the dystonia initially present in the patient's upper extremity disappeared after the second application.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.4. Patient 4\u003c/h2\u003e\u003cp\u003eThe fourth patient (Pt4), born in November 2021, had global developmental delay and signs of spasticity following an intracranial hemorrhage. The patient's diagnosis was determined to be mixed-type CP, characterized by spastic diplegia and right-sided hemiparesis. Her first standardized clinical evaluation was done in December 2023 and included tests for spasticity, gross motor function, and muscle strength.\u003c/p\u003e\u003cp\u003eThe IM route was used to target key muscle groups including paraspinal extensors, quadriceps, tibialis anterior, deltoid, biceps, triceps, and the external oblique (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). When her spasticity was reassessed in December 2024, there was no significant change observed according to the MAS. All measured areas, shoulders, elbows, hands, hips, knees, and ankles maintained their original scores between 1 and 2, showing no improvement in muscle tone (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). However, she did improve in other ways. Her gross motor function remained stable, with already high MI scores staying consistent. Notably, her ability to shift from lying to sitting, which was absent before (score of 0), improved to a score of 14, suggesting a real gain in trunk stability and coordination (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Her muscle strength, which had already been quite good (between 4/5 and 5/5), improved further, reaching full strength (5/5) in both arms and legs by the final follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). No range-of-motion limitations were noted either before or after therapy (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBeyond these scores, her family and clinicians noted clear improvements in day-to-day function. She became more responsive to verbal commands, began producing intentional sounds, and gained better head and body control. She also started to recognize voices and interact more emotionally. Crawling posture became possible, and there was a clear drop in secretions and respiratory issues. Overall, the therapy was well-tolerated, with no AEs reported.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline Demographics and Clinical Characteristics of the Four Pediatric Patients with Spastic CP\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBirth Date\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDiagnosis / Cause\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eInitial Evaluation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFollow-up Date\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMSC Doses\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eRoutes of Administration\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eTargeted Muscles (IM injections)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAug 2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCP (Spastic, HIE)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMar 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eJan 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6 sessions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIV\u0026thinsp;+\u0026thinsp;IT\u0026thinsp;+\u0026thinsp;IM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eParaspinals, Quadriceps, Tibialis Ant., Deltoid, Ext. Oblique\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMay 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCP (Spastic and dyskinetic)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFeb 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6 sessions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIV\u0026thinsp;+\u0026thinsp;IT\u0026thinsp;+\u0026thinsp;IM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eParaspinals, Quadriceps, Tibialis Ant., Deltoid, Biceps, Triceps, Hip Adductors\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eJul 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCP (Spastic diplegic type, mild symptoms)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSep 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMar 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6 sessions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIV\u0026thinsp;+\u0026thinsp;IT\u0026thinsp;+\u0026thinsp;IM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eParaspinals, Hip Ext/Abd, Quadriceps, Deltoid, Gluteus Medius, Peroneals\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNov 2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCP (Mixed type, Intracranial Hemorrhage)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDec 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDec 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6 sessions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIV\u0026thinsp;+\u0026thinsp;IT\u0026thinsp;+\u0026thinsp;IM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eParaspinals, Quadriceps, Tibialis Ant., Deltoid, Biceps, Triceps, Ext. Oblique\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePre- and Post-Treatment Clinical Outcomes Following UC-MSC Therapy in Pediatric CP Patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMAS (Pre)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMAS (Post)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMI Arm (Pre\u0026rarr;Post)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMI Leg (Pre\u0026rarr;Post)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTCT (Pre\u0026rarr;Post)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMRC (Pre\u0026rarr;Post)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eQualitative Gains\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (hands, knees, elbows)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (hands, knees, elbows)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 \u0026rarr; 49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42 \u0026rarr; 57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSit-up: 0\u0026rarr;14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3\u0026ndash;4/5 \u0026rarr; 5/5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBetter posture, motor control, full limb power.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u0026ndash;4 (upper and lower limbs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u0026thinsp;+\u0026thinsp;to 1 (upper limbs/hip)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38 \u0026rarr; 55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33 \u0026rarr; 47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRoll: 0\u0026rarr;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3\u0026ndash;4/5 \u0026rarr; 5/5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eGains in cognition, emotion, and motor control. Patient\u0026rsquo;s dystonia disappeared.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (upper limbs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (all limbs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 \u0026rarr; 99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32 \u0026rarr; 57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSit-up: 0\u0026rarr;14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3\u0026ndash;4/5 \u0026rarr; 5/5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eImproved postural control, emotional interaction. Patient\u0026rsquo;s upper limb dystonia disappeared\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePt4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u0026ndash;2 (all limbs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh \u0026rarr; High\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh \u0026rarr; High\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSit-up: 0\u0026rarr;14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4\u0026ndash;5/5 \u0026rarr; 5/5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHead control, vocalization, crawling posture.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe present case series demonstrates that children with spastic CP can clinically significantly benefit from UC-MSC treatment. Improvements in at least one of the assessed domains\u0026mdash;spasticity, muscle strength, motor function, trunk control, and daily functional interaction\u0026mdash;were observed among all four patients at the end of 10\u0026ndash;12 months follow-up period. Significantly, no adverse outcomes were observed during the six-session treatment course, supporting the safety of the cell therapy which is in parallel with previous studies on MSC use in pediatric populations.\u003c/p\u003e\u003cp\u003ePatients 1 to 3 showed reductions in spasticity identified by the MAS, with muscle tone scores falling by 1\u0026ndash;2 points across groups of upper and lower limbs. Particularly patient 3 showed total spasticity recovery. The disappearance of the pronounced dystonias observed in the neurological examinations of Pt2 and Pt3 prior to stem cell treatment in the second and third applications can be explained by the variability of the patients' anti-inflammatory responses. Across the cohort, there were notable increases in gross motor function measured using the MI and TCT. Especially, sit-to- stand transition and trunk coordination which are two important markers of central motor control, improved in patients 1, 2, and 4, supporting the suggestion that MSCs may enhance neural circuit plasticity [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn MRC scale evaluations, all four patients demonstrated improvements in muscle strength; at follow-up, they achieved either near or full grade 5 strength. Patient 4 showed improved head and postural control even though her MAS scores did not change from lying to sitting. This draws attention to a possible dissociation between spasticity reduction and functional recovery, a finding consistent with previous studies implying that MSCs may have neuromodulating properties beyond solely tone management [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study has several limitations that should be acknowledged. Firstly, the small sample size reduces the generalizability of the outcomes and makes it difficult to separate treatment effects from normal developmental progression without having a comparison group. The individualized nature of functional improvements also introduces variability that may not be fully captured by standardized scoring systems. Furthermore, even if caregiver-reported outcomes provide insightful analysis of qualitative changes, they are still subjective and would benefit from further validation via blinded assessments. An additional crucial factor is the financial obstacle related to cell therapies. Cell-based advanced therapy medicinal products' expensive manufacturing and clinical application costs not only limit their general accessibility but also could explain the limited cohorts in many of such trials. Expanding access depends on addressing cost-related issues, particularly in countries with low or middle incomes where the burden of CP remains disproportionately high. Comprehensive evaluation of the therapeutic potential and scalability of MSC treatment for CP requires longer-term follow-up research with larger, randomized cohorts and cost-effective analyses.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis case series adds to the accumulating data supporting the safety and potential efficacy of UC-MSC therapy for pediatric patients with spastic CP. Each patient in this small cohort demonstrated substantial improvements in muscle tone, strength, mobility, or daily interactions, highlighting how cell therapies may give hope to families navigating the difficulties of CP. Although the outcomes were optimistic, particularly in terms of functional gains and quality of life enhancements, it is important to acknowledge variations between individuals in response. One contributing factor to the small cohort size in such clinical studies is the high cost of cell-based advanced therapeutical medicinal products, which limits broader accessibility. Reducing the manufacturing costs and making these treatments more accessible could offer renewed hope to children and families affected by CP worldwide, particularly in resource-limited settings. Results of this study highlight the need of more extensive and controlled clinical studies to accurately define the therapeutic potential of MSCs and direct their future application in pediatric neurorehabilitation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval: Mesenchymal stem cell products were obtained from the LivMedCell Good Manufacturing Practice (GMP) facility located in Istanbul, Turkey. The umbilical cord was acquired from multiple donors after obtaining their informed consent, in accordance with the authorization of the institutional regulatory board. All cell therapy applications were performed following informed consent of the patient.\u003c/p\u003e\n\u003cp\u003eClinical trial number: Not applicable (Clinical applications in this study were approved by the Turkish Ministry of Health, the Department of Organ/Tissue Transplantation and Dialysis Services under the General Directorate of Health Services and its Scientific Committee (Approval Document Number: E-56733164-203-249680398, E-56733164-203-216374168, E-56733164-203-222165075, and E-56733164-203-228661723).\u003c/p\u003e\n\u003cp\u003eConsent to participate: All authors confirm their full participation in the preparation and submission of the manuscript titled \u0026ldquo;Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy\u0026quot; to the Stem Cell Reviews and Reports Journal. All authors have contributed intellectually to the manuscript, reviewed its content, and consented to its submission. The corresponding author (Ayberk Akat, Ph.D.) is authorized to communicate with the journal on behalf of all authors.\u003c/p\u003e\n\u003cp\u003eConsent for publication: All authors approve the final version of the manuscript for publication. They consent to the publication of relevant personal information (such as name, affiliation) in accordance with journal policies.\u003c/p\u003e\n\u003cp\u003eAvailability of data and material: The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: GK: Comprehensive evaluation of patients, analysis of test results, performed neurological examinations, applied cell therapies, and conducted follow-ups to monitor the patients\u0026rsquo; progress. Her expertise and dedication were pivotal in managing the patients care throughout the treatment period. AA: Quality control analysis of cell therapy products applied to the patients, collected data, analyzed results, and drafted the article. ON\u0026Ouml;: Responsible for production of clinical grade cell therapy products applied to the patients, collected data, analyzed results, and drafted the article. \u0026Ccedil;\u0026Ouml;: Evaluation of patients, application of cell therapy products, and conducted follow-ups to monitor the patients\u0026rsquo; progress. MC: Physical therapy, rehabilitation and evaluation of the patients, conducted follow-ups to monitor the patients\u0026rsquo; progress. EK: Study conception and design, responsible for the production of cell therapy products, revised the article critically for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVitrikas K, Dalton H, Breish D (2020) Cerebral Palsy: An Overview. Am Family Phys 101(4):213\u0026ndash;220\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcIntyre S, Goldsmith S, Webb A, Ehlinger V, Hollung SJ, McConnell K, Arnaud C, Smithers-Sheedy H, Oskoui M, Khandaker G, Himmelmann K, Global CP, Prevalence Group (2022) Global prevalence of cerebral palsy: A systematic analysis. Dev Med Child Neurol 64(12):1494\u0026ndash;1506. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/dmcn.15346\u003c/span\u003e\u003cspan address=\"10.1111/dmcn.15346\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDelobel-Ayoub M, Ehlinger V, Klapouszczak D, Troha Gergeli A, Sellier E, Hollody K, Virella D, Vik T, Perret C, Vidart d'Egurbide Bagazgo\u0026iuml;tia, Horridge N, K., Arnaud C (2025) Postneonatal Cerebral Palsy in Europe: Prevalence and Clinical Characteristics According to Contributory Events: An SCPE Study. Pediatric and perinatal epidemiology, 39(3), 287\u0026ndash;298. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/ppe.13164\u003c/span\u003e\u003cspan address=\"10.1111/ppe.13164\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, Dan B, Jacobsson B (2007) A report: the definition and classification of cerebral palsy April 2006. Supplement 109:8\u0026ndash;14Developmental medicine and child neurology\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcCoy SW, Palisano R, Avery L, Jeffries L, Laforme Fiss A, Chiarello L, Hanna S (2020) Physical, occupational, and speech therapy for children with cerebral palsy. Dev Med Child Neurol 62(1):140\u0026ndash;146. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/dmcn.14325\u003c/span\u003e\u003cspan address=\"10.1111/dmcn.14325\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReilly M, Liuzzo K, Blackmer AB (2020) Pharmacological Management of Spasticity in Children with Cerebral Palsy. J Pediatr health care: official publication Natl Association Pediatr Nurse Associates Practitioners 34(5):495\u0026ndash;509. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.pedhc.2020.04.010\u003c/span\u003e\u003cspan address=\"10.1016/j.pedhc.2020.04.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStasolla F, Caff\u0026ograve; AO, Perilli V, Boccasini A, Damiani R, D'Amico F (2019) Assistive technology for promoting adaptive skills of children with cerebral palsy: ten cases evaluation. Disabil Rehabil Assist Technol 14(5):489\u0026ndash;502. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/17483107.2018.1467972\u003c/span\u003e\u003cspan address=\"10.1080/17483107.2018.1467972\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuc Lien N, Van Linh N, Van C, Giang NT, King LT, Tarren DT, Dat A, N. D., Rocque BG (2024) Selective Dorsal Rhizotomy for Spastic Cerebral Palsy: Report of 18 Cases Performed in the North of Vietnam. World Neurosurg 188:e128\u0026ndash;e133. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.wneu.2024.05.055\u003c/span\u003e\u003cspan address=\"10.1016/j.wneu.2024.05.055\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTheroux MC, DiCindio S (2014) Major surgical procedures in children with cerebral palsy. Anesthesiol Clin 32(1):63\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.anclin.2013.10.014\u003c/span\u003e\u003cspan address=\"10.1016/j.anclin.2013.10.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAkat A, Kara\u0026ouml;z E (2025) A systematic review of cell therapy modalities and outcomes in cerebral palsy. Mol Cell Biochem 480(2):891\u0026ndash;922. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11010-024-05072-3\u003c/span\u003e\u003cspan address=\"10.1007/s11010-024-05072-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGu J, Huang L, Zhang C et al (2020) Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial. Stem Cell Res Ther 11:43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13287-019-1545-x\u003c/span\u003e\u003cspan address=\"10.1186/s13287-019-1545-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVankeshwaram V, Maheshwary A, Mohite D, Omole JA, Khan S (2020) Is Stem Cell Therapy the New Savior for Cerebral Palsy Patients? Rev Cureus 12(9):e10214. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7759/cureus.10214\u003c/span\u003e\u003cspan address=\"10.7759/cureus.10214\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen W, Ren Q, Zhou J, Liu W (2024) Mesenchymal Stem Cell-Induced Neuroprotection in Pediatric Neurological Diseases: Recent Update of Underlying Mechanisms and Clinical Utility. Appl Biochem Biotechnol 196(9):5843\u0026ndash;5858. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12010-023-04752-y\u003c/span\u003e\u003cspan address=\"10.1007/s12010-023-04752-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmanat M, Majmaa A, Zarrabi M et al (2021) Clinical and imaging outcomes after intrathecal injection of umbilical cord tissue mesenchymal stem cells in cerebral palsy: a randomized double-blind sham-controlled clinical trial. Stem Cell Res Ther 12:439. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13287-021-02513-4\u003c/span\u003e\u003cspan address=\"10.1186/s13287-021-02513-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAkhlaghpasand M, Hosseinpou M, Hajikarimloo B, Hajirajizadeh A, Golmohammadi M, Tavaneei R, Mohammad1 I, Angoharibari NA, MohammadEbrahim N, Zali A, Oraee-Yazdani S (2025) Repeated intrathecal injections of autologous bone marrow-derived mesenchymal stem cells for spastic cerebral palsy: Single-arm safety and preliminary efficacy clinical trial. Journal of Neurorestoratology, 2025, 100207. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jnrt.2025.100207\u003c/span\u003e\u003cspan address=\"10.1016/j.jnrt.2025.100207\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFinch-Edmondson M, Paton MCB, Honan I, Karlsson P, Stephenson C, Chiu D, Reedman S, Griffin AR, Morgan C, Novak I (2022) Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy. J Clin Med 11(24):7319. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jcm11247319\u003c/span\u003e\u003cspan address=\"10.3390/jcm11247319\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQu J, Zhou L, Zhang H, Han D, Luo Y, Chen J, Li L, Zou Z, He Z, Zhang M, Ye J (2022) Efficacy and safety of stem cell therapy in cerebral palsy: A systematic review and meta-analysis. Front Bioeng Biotechnol 10:1006845. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fbioe.2022.1006845\u003c/span\u003e\u003cspan address=\"10.3389/fbioe.2022.1006845\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eH\u0026uuml;zmeli H, Akat A, \u0026Ouml;zkara A, Ceylan E, \u0026Ouml;zen\u0026ccedil; E, Kara\u0026ouml;z E (2025) Extracellular Vesicle-Enhanced Stem Cell Therapy in Acute Myocardial Infarction: A Case Report of Cardiac Regeneration from a Bypass Surgery. Stem Cell Rev Rep. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12015-025-10910-y\u003c/span\u003e\u003cspan address=\"10.1007/s12015-025-10910-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBohannon RW, Smith MB (1987) Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 67(2):206\u0026ndash;207. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/ptj/67.2.206\u003c/span\u003e\u003cspan address=\"10.1093/ptj/67.2.206\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDemeurisse G, Demol O, Robaye E (1980) Motor evaluation in vascular hemiplegia. Eur Neurol 19(6):382\u0026ndash;389. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000115178\u003c/span\u003e\u003cspan address=\"10.1159/000115178\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFranchignoni FP, Tesio L, Ricupero C, Martino MT (1997) Trunk control test as an early predictor of stroke rehabilitation outcome. Stroke 28(7):1382\u0026ndash;1385. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/01.str.28.7.1382\u003c/span\u003e\u003cspan address=\"10.1161/01.str.28.7.1382\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMedical Research Council (1976) Aids to the examination of the peripheral nervous system (Memorandum No. 45). Her Majesty's Stationery Office\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang X, Kuang Q, Xu J, Lin Q, Chi H, Yu D (2024) MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research. Biomolecules 14(5):538. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/biom14050538\u003c/span\u003e\u003cspan address=\"10.3390/biom14050538\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi M, Chen H, Zhu M (2022) Mesenchymal stem cells for regenerative medicine in central nervous system. Front Neurosci 16:1068114. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fnins.2022.1068114\u003c/span\u003e\u003cspan address=\"10.3389/fnins.2022.1068114\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeo JH, Cho SR (2012) Neurorestoration induced by mesenchymal stem cells: potential therapeutic mechanisms for clinical trials. Yonsei Med J 53(6):1059\u0026ndash;1067. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3349/ymj.2012.53.6.1059\u003c/span\u003e\u003cspan address=\"10.3349/ymj.2012.53.6.1059\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang P, Gebhart N, Richelson E, Brott TG, Meschia JF, Zubair AC (2014) Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation. Cytotherapy 16(10):1336\u0026ndash;1344. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jcyt.2014.05.007\u003c/span\u003e\u003cspan address=\"10.1016/j.jcyt.2014.05.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cerebral Palsy, Mesenchymal Stem Cells, Motor Function, Spasticity, Stem Cell Therapy","lastPublishedDoi":"10.21203/rs.3.rs-7202210/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7202210/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCerebral palsy is a non-progressive neurodevelopmental disorder often caused by hypoxic ischemic encephalopathy or intracranial hemorrhage, resulting in motor dysfunction and spasticity. While current treatments focus on symptomatic relief, mesenchymal stem cell therapy has emerged as a promising regenerative strategy with neuroprotective and neurorestorative potential.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo evaluate the functional and neurological outcomes following umbilical cord-derived mesenchymal stem cell therapy in four pediatric patients with spastic cerebral palsy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis multicenter case series included four children diagnosed with cerebral palsy secondary to hypoxic ischemic encephalopathy or intracranial hemorrhage. Each patient received six sessions of cell therapy via intrathecal, intravenous, and intramuscular routes. Clinical assessments were performed before and after therapy using the Modified Ashworth Scale, Motricity Index, Trunk Control Test, and Medical Research Council Muscle Strength Scale.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAll patients demonstrated improvements in at least one clinical domain. Three patients showed reduced spasticity, improved trunk control, and increased muscle strength. Functional motor scores improved remarkably in most cases, particularly in sit-to-stand transitions and voluntary limb movements. One patient, despite unchanged spasticity scores, exhibited functional gains in posture, head control, and cognitive-emotional interactions. No adverse events were reported in any of the participants.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eMesenchymal stem cell therapy was well-tolerated and associated with functional improvements and reduced spasticity in children with spastic cerebral palsy at the end of 10\u0026ndash;12 months follow-up. These findings support the potential of mesenchymal stem cell-based interventions in pediatric neurorehabilitation and underscore the need for further large-scale trials to validate efficacy, explore cost-efficiency, and enable global accessibility.\u003c/p\u003e","manuscriptTitle":"Restoring Motion: A Case Series on the Functional and Spasticity Outcomes of MSC Therapy in Cerebral Palsy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-15 06:27:06","doi":"10.21203/rs.3.rs-7202210/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d4bbada-0f93-4ee8-9e57-182d96c3a39a","owner":[],"postedDate":"September 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T08:09:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-15 06:27:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7202210","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7202210","identity":"rs-7202210","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}