Brief Summary This clinical study investigates the safety and effectiveness of combining advanced regenerative therapies with personalized surgical technology for patients with delayed fracture healing (non-unions), knee osteoarthritis, and those requiring total knee replacement.

Scientific rationale Bone fractures sometimes heal slowly or fail to unite despite standard treatment, and knee osteoarthritis causes progressive cartilage loss, pain, and disability. Mesenchymal stromal cells (MSCs) are multipotent cells with well-documented ability to promote bone formation, modulate inflammation, and support tissue repair. Platelet-rich plasma (PRP), prepared from the patient's own blood, delivers concentrated growth factors that accelerate healing and reduce inflammation. Both therapies are supported by multiple clinical studies showing their potential to improve fracture union rates and relieve osteoarthritis symptoms. For patients undergoing knee replacement, the study uses patient-specific 3D-printed surgical instruments (cutting guides) created from the individual's CT or MRI scans. These custom tools have been shown in scientific literature to improve implant positioning accuracy compared with conventional methods.

Safety All three technologies have favorable safety profiles. MSCs and PRP are autologous (derived from the patient), which greatly reduces the risk of immune reactions or disease transmission. Clinical trials have reported no serious treatment-related adverse events, such as tumor formation or systemic complications, with these regenerative approaches. The 3D-printed instruments are biocompatible and designed specifically for each patient, with studies confirming they do not increase perioperative risks.

Study procedures (high-level overview) Participants with delayed fracture healing receive a single minimally invasive injection of MSCs combined with PRP directly at the fracture site under local anesthesia or light sedation. Patients with knee osteoarthritis undergo intra-articular injections of the same MSC-PRP combination into the affected joint, usually performed in an outpatient setting. For those scheduled for total knee arthroplasty, the surgery is performed using patient-specific 3D-printed navigation guides that are placed on the bone surfaces to ensure precise bone cuts and optimal implant positioning. All procedures are carried out by experienced orthopedic surgeons following standard sterile techniques.

Advantages The combination aims to offer several potential benefits: faster and more reliable bone healing in delayed fractures, reduced pain and improved joint function in osteoarthritis, and greater precision during knee replacement surgery, which may lead to better long-term implant stability, shorter operation time, less blood loss, and faster recovery. By integrating regenerative biology with personalized surgical navigation, this study evaluates a modern, patient-centered approach that may improve outcomes while minimizing complications.

The primary goal is to assess whether this integrated strategy enhances healing rates, reduces pain, improves mobility, and raises quality of life for patients with these challenging orthopedic conditions.

This clinical study evaluates an integrated approach combining regenerative medicine technologies and personalized surgical navigation for the treatment of two major orthopedic conditions: delayed fracture healing (including non-unions) and knee osteoarthritis, including cases requiring total knee arthroplasty.

Background and Scientific Rationale Delayed fracture healing and non-unions remain significant clinical challenges despite advances in surgical fixation. Similarly, knee osteoarthritis is a leading cause of pain, disability, and reduced quality of life due to progressive cartilage degeneration and subchondral bone changes. Conventional treatments often provide only symptomatic relief or require invasive surgery with variable long-term outcomes.

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells capable of differentiating into osteoblasts and chondrocytes, secreting paracrine factors that promote angiogenesis, modulate inflammation, and stimulate endogenous repair mechanisms. Platelet-rich plasma (PRP), an autologous concentrate of platelets and growth factors (including PDGF, TGF-β, VEGF, and IGF-1), enhances MSC activity and accelerates tissue regeneration. Extensive preclinical and clinical evidence supports the combined use of MSCs and PRP for bone regeneration in delayed unions and for intra-articular cartilage protection and pain relief in osteoarthritis.

For patients indicated for total knee replacement, the study incorporates patient-specific 3D-printed surgical instruments (custom cutting guides and navigation templates) fabricated from the individual's preoperative CT or MRI scans. These instruments enable highly accurate bone resections and implant positioning, which has been shown in peer-reviewed literature to reduce outliers in alignment, decrease operative time, lower blood loss, and potentially improve functional recovery compared with standard instrumentation.

The rationale for this integrated strategy is to harness the biological regenerative potential of autologous MSC-PRP therapy while optimizing mechanical precision through 3D-printed patient-specific tools, thereby addressing both biological and technical aspects of orthopedic repair in a single patient-centered protocol.

Safety Profile MSCs and PRP are autologous products, minimizing immunogenicity and the risk of disease transmission. Published clinical trials have consistently demonstrated a favorable safety profile with no reports of serious adverse events such as tumorigenesis, ectopic bone formation, or systemic complications attributable to the therapy. The 3D-printed instruments are manufactured from biocompatible medical-grade materials and undergo sterilization according to standard hospital protocols. No increased perioperative risks have been associated with their use in prior studies.

Study Procedures

For delayed fracture healing: Participants receive a single ultrasound- or fluoroscopy-guided percutaneous injection of autologous MSCs combined with PRP directly into the fracture site under local anesthesia or light sedation.

For knee osteoarthritis: Participants undergo one or more intra-articular injections of the MSC-PRP combination into the affected knee joint, performed in an outpatient setting under local anesthesia.

For total knee arthroplasty: Surgery is conducted using patient-specific 3D-printed navigation guides placed on the femoral and tibial surfaces to guide precise bone cuts and ensure optimal implant alignment. Standard surgical approaches and implant systems are used in combination with the custom guides.

All interventions are performed by board-certified orthopedic surgeons in accordance with Good Clinical Practice and institutional sterile techniques. Follow-up assessments include clinical evaluation, radiographic imaging, and patient-reported outcome measures to monitor healing, pain, function, and safety.

Potential Advantages This combined regenerative and personalized surgical approach offers several theoretical and practical benefits: accelerated and more reliable bone consolidation in delayed fractures, symptomatic relief and possible disease modification in knee osteoarthritis, and enhanced precision in knee replacement surgery leading to better implant longevity, reduced complications, shorter hospital stays, and faster return to daily activities.

By integrating biological augmentation with state-of-the-art 3D-printed navigation, the study aims to provide a modern, minimally invasive, and highly individualized treatment pathway that may improve clinical outcomes while maintaining an excellent safety profile.

Inclusion Criteria:

Male or female patients aged 18 to 80 years inclusive

Diagnosis of one of the following orthopedic conditions:

Delayed fracture healing or established non-union of a long bone fracture (at least 6 months after initial injury, confirmed radiographically) Symptomatic knee osteoarthritis (Kellgren-Lawrence grade 2-4) Indication for primary unilateral total knee arthroplasty due to osteoarthritis

Willing and able to provide written informed consent Able to comply with the study protocol, follow-up visits, and required examinations

Exclusion Criteria:

Active infection at the injection or surgical site, systemic infection, or history of recurrent infections Known malignancy or history of malignancy within the past 5 years (except basal cell carcinoma) Autoimmune or inflammatory rheumatic disease requiring systemic immunosuppressive therapy Uncontrolled diabetes mellitus (HbA1c > 9.0%) Severe cardiovascular, renal, hepatic, or pulmonary disease that, in the investigator's opinion, makes the patient unsuitable for participation Pregnancy, breastfeeding, or unwillingness to use effective contraception during the study period Previous knee surgery (except diagnostic arthroscopy) in the target knee (for osteoarthritis and TKA groups) Contraindications to bone marrow aspiration or blood draw for PRP preparation Participation in another clinical trial within 30 days prior to screening Any medical condition that, in the investigator's judgment, would interfere with the assessment of safety or efficacy