Evaluation of Efficacy and Safety of Autologous MSCs Combined to Biomaterials to Enhance Bone Healing

Study Overview
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Brief Summary
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Bone grafting is widely used in hospitals to repair injured, aged or diseased skeletal tissue. In Europe, about one million patients encounter a surgical bone reconstruction annually and the numbers are increasing due to our ageing population. Bone grafting intends to facilitate bone healing through osteogenesis (i.e. bone generation) at the site of damage, but this is only attained presently by including cells capable of forming bone into the augmentation. Bone autograft is the safest and most effective grafting procedure, since it contains patient's own bone growing cells (to enhance osteogenesis) and proteins (to enhance osteoinduction), and it providing a scaffold for the new bone to grow into (osteoconduction). However, bone autograft is limited in quantity (about 20 cc) and its harvesting (e.g. from the iliac crest) represents an additional surgical intervention, with frequent consequent pain and complications. We hypothesize that using autologous bone marrow cells expanded in GMP facility surgically implanted with synthetic bone substitutes contribute to the resolution of the health and socioeconomic complications of delayed union or non-union after diaphyseal and metaphyseal-diaphyseal fractures with safety and efficacy.

Detailed Description
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Tissue engineering combines bone marrow cells or mesenchymal stem cells (MSCs), synthetic scaffolds and molecular signals (growth or differentiating factors) in order to form hybrids constructs. For bone reconstruction purposes, human MSCs have been seeded and cultured on porous calcium phosphate ceramics in osteogenic media. Some clinical studies with low numbers of patients have been reported using this approach but the outcomes were inconsistent with low efficacy in bone regeneration. The reasons of the limited clinical success may be due to several bottlenecks in the multidisciplinary field of bone tissue engineering. The association in vitro of biomaterials and osteoprogenitor cells raises technical challenges and regulatory and ethic issues for the implementation of clinical trials, whereas the expansion of MSCs is now possible in GMP Facility. The expected results are to obtain bone consolidation thus healing of delayed union or non-union, as proven by imaging techniques, without using bone graft. This will prove the efficacy of the proposed IMP based on pluripotent MSCs expanded in a GMP facility and mixed with granulated biphasic calcium phosphate in the surgical setting before implantation. No expected complications related to the procedure are expected. Changes in serum levels of bone turnover markers will be described.

Official Title
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Evaluation of Efficacy and Safety of Autologous MSCs Combined to Biomaterials to Enhance Bone Healing in Patients With Delayed Consolidation After Long Bone Fracture Requiring Graft Apposition or Alternative Orthobiologics

Conditions
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Delayed Union After Fracture of Humerus, Tibial or Femur

Intervention / Treatment
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* Procedure: Implantation of bone substitute plus autologous cultured mesenchymal cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 65, both sexes Traumatic isolated closed or open Gustilo I and II humerus, tibial or femur diaphyseal or metaphyseal-diaphyseal fracture status delayed union or non-union At least 3 months from acute fracture Able to provide informed consent, and signed informed consent Patients (by themselves) should have medical health care coverage to be included in a research study Able to understand and accept the study constraints Exclusion Criteria: Pregnancy, breast feeding women and women who are of childbearing age and not practicing adequate birth control Participation in another therapeutic trial in the previous 3 months Delayed union or non-union related to iatrogeny Segmental bone loss requiring specific therapy (bone transport, large structural allograft, megaprosthesis, etc) Vascular or neural injury Other fractures causing interference with weight bearing Acute persistent chronic bacterial infections such as brucellosis, typhus, leprosy, relapsing fever, melioidosis and tularemia Visceral injuries of diseases interfering with callus formation (cranioencephalic trauma, etc.) History of bone harvesting on iliac crest contraindicating bone-marrow aspiration Corticoid or immunosuppressive therapy more than one week in the three months prior to study inclusion History of prior or concurrent diagnosis of HIV-, Syphilis, Hepatitis-B- or Hepatitis-C-infection (confirmed by serology or PCR) History of neoplasia or current neoplasia in any organ Subject legally protected, under legal guardianship, deprived of their liberty by judicial or administrative decision, subject of psychiatric care, or admission to a health facility. Impossibility to meet at the appointments for the follow up Insulin dependent diabetes Obesity (BMI > 30) Autoimmune inflammatory disease Current treatment by biphosphonate or stopped in the three months prior to study inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Implantation surgery<br>All the patients will have the implantation surgery. This trial is a one-arm study. | Procedure: Implantation of bone substitute plus autologous cultured mesenchymal cells<br>* Implantation surgery of a synthetic bone substitute associated with autologous bone marrow cells expanded<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complication rate as percentage of patients with local complications regarding the non-union treatment in the follow-up |  | At 6 weeks, 12 weeks, 24 weeks and 52 weeks after the implantation surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with proven bone healing |  | 6 weeks, 12 weeks, and 24 weeks after the implantation surgery | 
| Amount of radiological callus |  | 6 weeks, 12 weeks, and 24 weeks after the implantation surgery | 
| Clinical consolidation |  | 6 weeks, 12 weeks, and 24 weeks after implantation surgery | 
| No reoperation done or scheduled |  | 24 weeks after implantation surgery | 
| Changes in serum levels of bone turnover markers |  | 6 weeks, 12 weeks, and 24 weeks after the implantation surgery |