Bone Tissue Engineering Using Autologous Bone Repair Cell (BRC) Therapy for Sinus Floor Bone Augmentation

Study Overview
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Brief Summary
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The purpose of this research is to determine if one's own bone marrow tissue can help regenerate (grow) bone in the area of the jaw where an implant will be placed. The name of the process is called Bone Repair Cell (BRC) Therapy. A sample of bone marrow tissue will be collected and sent to a laboratory where it will be processed to form more cells. These new cells will then be transplanted in the regenerative site or sinus floor augmentation site. The researchers are testing to see if these cells (BRC) will help form bone indicating. The research will also determine if the implant will be more stable in the area with new bone growth.

Detailed Description
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The overall aim is to promote bone regeneration, using Aastrom's proprietary Adult Stem Cell Therapy (AST) developed collaboratively with the University of Michigan, to enable placement of dental implants in patients who lack adequate alveolar bone. This project addresses specifically the placement of dental implants following bone regenerative sinus floor augmentation. This novel therapy mitigates the risks of other therapies, providing additional benefits of adequate cell numbers for high quality bone regeneration, and has the potential to become the new standard of care. In Aastrom's patented manufacturing technology, iliac bone marrow aspirates are expanded ex-vivo to enrich for adult multipotent cells (Bone Repair Cells- BRC) capable of regenerating bone and blood vessels. BRC will then be mixed with bone matrix graft extender, beta-tricalcium phosphate (β-TCP), before their implantation into the regenerative site.

Official Title
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Cell Therapy Using Autologous Bone Marrow Cells Expanded Ex Vivo and Delivered Using Tricalcium Phosphate

Conditions
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Tooth Loss

Intervention / Treatment
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* Procedure: Sinus lift augmentation and dental implant
* Biological: Aastrom BRCs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range: 20-70 yrs Gender: Male and female Systemically healthy: Physical status according to the American Society of Anesthesiologists (ASA) I or II Requiring sinus augmentation to allow dental implant placement Missing teeth: Maxillary second premolar, maxillary first molar and/or maxillary second molar Remaining alveolar bone height: 2 to 6 mm Must be able and willing to follow study procedures and instructions Must have read, understood and signed an informed consent form Exclusion Criteria: Allergies or hypersensitivities to study related medications: dexamethasone, chlorhexidine, ibuprofen. For patients allergic to amoxicillin a comparable substitute antibiotic will be used Hematologic disorders/ blood dyscrasias Active infectious disease Liver or kidney dysfunction/failure- Patients will have blood drawn for serum laboratory tests, including creatinine, blood urea nitrogen, AST, ALT, and bilirubin. All of these must be within normal limits for a patient to be included in the study Laboratory values that will define normal renal and hepatic function, as well as criteria for exclusion of metabolic bone disease are consistent with those established by the University of Michigan Health System (UMHS). Normal clinical values will be used to help assure the health of all subjects in this trial. Potential subjects whose laboratory values fall outside the UMHS normal ranges and are considered clinically significant will be required to have medical clearance from their primary care provider prior to participation. Potential subjects presenting with clinically insignificant laboratory abnormalities will not require medical clearance and will be considered for inclusion in the study Endocrine disorders/dysfunctions (i.e. Type I and II diabetes) Cancer - The explicit definition of cancer used to exclude patients is consistent with that described by the National Cancer Institute (NCI), National Institutes of Health. According to NCI, cancer is any disease in which abnormal cells divide without control and invade nearby tissues (invasive disease). These include carcinomas, sarcomas, leukemias, and lymphomas. Any patient with a history of these invasive diseases will be excluded from the study. Patients who currently use bisphosphonates or have a history of bisphosphonate use will be excluded from the trial HIV+ Metabolic Bone Diseases- Patients with metabolic bone diseases such as Paget's disease, hypercalcemia, moderate to severe vitamin D3 abnormalities or any other metabolic bone disease including osteoporosis and osteoporotic fractures will be excluded Pregnant women- Female patients who are of childbearing potential are excluded except those who are using hormonal or barrier methods of birth control (oral or parenteral contraceptives, diaphragm plus spermicide, or condoms). Pregnancy status will be determined with a urine test and patients who are pregnant will be excluded Patients with acute sinusitis, or presenting any sinus pathology that would contraindicate sinus augmentation Patients with congenital or metabolic bone disorders Current smokers (have smoked within 6 mos. of study onset) Subjects with congenital, or co-morbid conditions that would affect the study outcome or interpretation of study results will be excluded Individuals who have a BMI outside normal limits that deems them overweight (BMI >25) will be excluded due to potential difficulties in locating appropriate surgical entry of the iliac crest during the bone marrow aspiration procedure Long term (>2 weeks) use of antibiotics in the past 3 months Periodontally unstable subjects Subjects having any extractions in the possible treatment area in the past 3 months Subjects that are edentulous

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: sinus lift plus dental implant<br>Transalveolar sinus augmentation will be performed. After 4 months dental implants will be delivered only if primary stability can be achieved. Intervention (Procedure/Surgery): Sinus lift augmentation and dental implant transalveolar sinus augmentation will be performed. After 4 months, dental implants will be delivered only if primary stability can be achieved. Biological/Vaccine: N/A; only sinus augmentation and dental implant | Procedure: Sinus lift augmentation and dental implant<br>* transalveolar sinus augmentation will be performed. After 4 months, dental implants will be delivered only if primary stability can be achieved.<br>|
| Experimental: sinus lift plus BRCs and dental implant<br>transalveolar sinus augmentation will be performed. A unit dose of BRC (10 ml) will be mixed with a commercially available β-TCP (Cerasorb), which will be used as a carrier to deliver the cells. Intervention (Procedure/Surgery): Sinus lift augmentation and dental implant transalveolar sinus augmentation will be performed. After 4 months, dental implants will be delivered only if primary stability can be achieved. Biological/Vaccine: Aastrom BRCs, sinus augmentation, BRC application, dental implant | Biological: Aastrom BRCs<br>* sinus augmentation, BRC application, dental implant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Mineral Density of Bone Core | Bone mineral density of bone core was measured by histological and µCT analyses | 4 months | 
| Bone Volume Fraction of Bone Core | Bone volume fraction of bone core histological and µCT analyses | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Linear Radiographic Bone Height | Change in linear radiographic bone heights were measured before and after bone graft reconstruction | Screening and 1 week post-op from baseline | 
| Change in Sinus Bone Volume | CBCT was used to evaluated 3-D changes in the bone volume within the treated areas of the sinus cavity | Pre-baseline and within 2 weeks of 4 Month visit | 
| Final Bone Volume: Initial Graft Volume Ratio | Bone volume fraction of bone core histological and µCT analyses | 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sinus lift, tooth extraction, dental implant