Biomaterials and Mesenchymal Stem/Stromal Cells in the Treatment of Knee Articular Surface Lesions

The goal of this observational study is to evaluate the combined single-step approach with biomaterials and mesenchymal stem/stromal cells in the treatment of knee articular surface lesions. The clinical analysis of the treatment outcomes, regarding postoperative improvements and safety, is going to be accompanied with laboratory analysis of the intraoperatively applied cellular products.

The main hypothesis are: (1) such combined single-step procedure significantly improves patients' functioning and quality of life; (2) this therapeutic approach is safe; (3) cellular parameters of the applied filtered bone marrow aspirate (fBMA) impact treatment outcomes, among other potential predictors.

Researchers will compare subjective (questionnaire) and objective (clinical examination) status of patients before and after the operation, record any potential complications and perform regression analysis to assess the influence of potential predictors on postoperative improvements.

Study Overview

• Status: Completed
• Conditions: Knee Injuries; Cartilage Injury; Osteochondral Defect
• Intervention / Treatment: Procedure: Biomaterials augmented with mesenchymal stem/stromal cells

• Study Type: Observational
• Enrollment (Actual): 90

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Centre Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

100-150 adult patients (age:18-65) with knee articular surface lesions (size ≥ 1.5 cm2, ICRS grades 3-4) surgically treated with the combined single-step approach (scaffold and fBMA) between January 2013 and December 2020.

Description

Inclusion Criteria:

• informed consent
• patients treated with combined single-step procedure (scaffold and fBMA) for knee articular surface lesions, between January 2013 and December 2020
• symptomatic knee articular surface lesions (International cartilage repair society (ICRS) grades 3-4, size ≥ 1.5 cm2) unresponsive to conservative treatment,
• only mild concomitant osteoarthritis (Kellgren-Lawrence grades 1-2)

Exclusion Criteria:

• patients that refuse to participate in the study
• non responders to the invitation to answer PROMs at the follow-up
• associated medical conditions (inflammatory, metabolic, neoplastic, etc.) that could directly handicap the musculoskeletal system or indirectly impact the quality of life

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Knee injury and Osteoarthritis Outcome Score (KOOS) subscale Pain postoperative improvement	Knee injury and Osteoarthritis Outcome Score (KOOS) assesses patients' pain (9 items), other symptoms (7 items), function in daily living (17 items), function in sport and recreation (5 items), and knee related quality of life (4 items). Scores range from 0 to 100 with a score 0 being the worst score and 100 indicating no impairment. KOOS subscale Pain postoperative improvement will be calculated as difference between preoperative and postoperative scores at the final follow up. Paired Student t test will be applied to compare preoperative and postoperative values of KOOS subscale Pain.	At least 24 months after the operation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Knee injury and Osteoarthritis Outcome Score (KOOS) subscales postoperative improvements	Originally published in 1998, the Knee injury and Osteoarthritis Outcome Score (KOOS) assesses patient pain (9 items), other symptoms (7 items), function in daily living (17 items), function in sport and recreation (5 items), and knee related quality of life (4 items). Scores range from 0 to 100 with a score 0 being the worst score and 100 indicating no impairment. KOOS subscales postoperative improvements will be calculated as differences between preoperative and postoperative scores at the final follow up. As secondary outcome measures will be calculated all KOOS subscales improvements, beside KOOS subscale Pain, which is determined as the primary outcome measure. Paired Student t test will be applied to compare preoperative and postoperative values of all KOOS subscales.	At least 24 months after the operation
Complications (SAE and GF)	Serious adverse events (SAE) are defined as any hospitalization or revision surgery (arthrofibrosis, synovitis, infection, hardware problem, pulmonary embolism, etc.), while graft failures (GF) as revision surgery to the lesion or confirmed indication for it. SAE will be further classified as related (arthrofibrosis, synovitis, graft hypertrophy/delamination, etc.) or unrelated (hardware removal, meniscus or ligament injuries, new cartilage lesions, pulmonary embolism, etc.) to the graft.	Recording until the final follow up (minimum 24 months after the operation)
Cellular parameters of intraoperatively applied filtered Bone Marrow Aspirate (fBMA)	Samples for cell counting (100 µl), fibroblast colony forming units (CFU-F) assay (1-2 ml) and flow cytometry (1-2 ml) will be taken before and after BMA processing with filter-based separation device. The total nucleated cell (TNC) count will be determined by counting white blood cells with hematology analyzer COULTER® Ac·T diff2™ (Beckman Coulter, Fullerton, CA, USA). MSCs content will be estimated with flow cytometry (FACSCalibur, BD Biosciences, San Jose, CA, USA) by determining CD271+ and CD45-cells, and concomitant assessment of their viability using 7-amino-actinomycin D (7-AAD) dye. Also, the CFU-F assay, which is a functional assay for measuring the frequency of MSCs with the colony forming abilities, will be performed. Briefly, cells will be seeded at least in duplicates into well culture plates and cultured in standard conditions: 37 °C, 5% CO2. After 14 days, colonies containing ≥ 50 fibroblastic cells will be manually counted under the stereomicroscope.	Finsihed in 14 days after the procedure
Tegner Activity Scale (TAS) postoperative improvement	Tegner Activity Scale (TAS) is a one-item score that graded activity based on work and sports activities on a 11-level scale from 0 to 10. Zero represents disability because of the knee problems and 10 represents national or international level soccer. TAS postoperative improvement will be calculated as difference between preoperative and postoperative scores at the final follow up. Paired Student t test will be applied to compare preoperative and postoperative values of TAS.	At least 24 months after the operation
European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) postoperative improvement	EQ-5D-3L descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression . Each dimension has 3 levels: no problems, some problems, and extreme problems. The respondent is asked to indicate his or her health state by ticking the box that marks the most appropriate level of problems in each dimension. A unique health state can be described according to the responses to the 5 questions. Health states defined in this way may be converted into a single summary index by applying a formula that attaches values to each of the levels in each dimension. States can be converted to a single value where 1 is equivalent to full health and 0 to a state equivalent to death. EQ-5D-3L postoperative improvement will be calculated as difference between preoperative and postoperative scores at the final follow up. Paired Student t test will be applied to compare preoperative and postoperative values of EQ-5D-3L .	At least 24 months after the operation
EuroQol Visual Analogue Scale (EQ-VAS) postoperative improvement	EQ-VAS records the patient's self-rated health on a vertical visual analogue scale from 0 to 100, where 0 represents the worst health state imaginable and 100 represents the best health state imaginable. EQ-VAS postoperative improvement will be calculated as difference between preoperative and postoperative scores at the final follow up. Paired Student t test will be applied to compare preoperative and postoperative values of EQ-VAS5.	At least 24 months after the operation
Potential predictors (patients' demographics, medical history, joint and lesions' characteristics, surgical and cellular parameters) of the clinical outcomes (KOOS subscales, EQ-5D-3L, EQ-VAS, TAS)	Regression models will be used to assess the influence of proposed predictors (patients' demographics, medical history, joint and lesions' characteristics, surgical and cellular parameters) on the postoperative improvements in clinical outcome measures (KOOS subscales, EQ-5D-3L, EQ-VAS, TAS). Statistical analysis will be performed with SPSS (version 25.0; IBM, Chicago, IL, USA).	At the time of statistical analysis

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Principal Investigator: Matic Kolar, MD, University Medical Centre Ljubljana

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: August 2, 2023
• First Submitted That Met QC Criteria: October 5, 2023
• First Posted (Actual): October 11, 2023

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Knee; Cartilage; Bone marrow aspirate; Biomaterials; Mesenchymal stem/stromal cells; Osteochondral lesion
• Additional Relevant MeSH Terms: Leg Injuries; Wounds and Injuries; Knee Injuries
• Other Study ID Numbers: University Medical Centre

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No