A Pilot Study to Demonstrate Safety and Feasibility of Cranial Reconstruction Using Mesenchymal Stromal Cells and Resorbable Biomaterials

Background: Cranial bone defects are often left following brain surgery, usually to allow swelling of the brain to recover before subsequently re-implanting a protective covering of the brain at a later time (cranioplasty). These procedures are performed anywhere over the cranial vault, either unilaterally or bilaterally. The original piece of bone (autologous bone plate = bone flap) is placed in a sterile container and stored in a refrigerator at temperature of -40oC.

Weeks or months later, when the brain is relaxed, the scalp well healed and the patient's medical condition permits, the individual is taken back to the operating room and the bone is reimplanted (A procedure known as an autologous cranioplasty). The aim of the procedure is to restore cosmesis and protection to the underlying brain and it can sometimes also improve neurological symptoms by unknown mechanisms. Unfortunately these aims are not always achieved and whilst technically straightforward the procedure is known to be associated with a number of complications. Two of the most significant of these are infection (such that the bone flap needs to be removed and replaced) and resorption (such that the protective function is compromised). Overall 10% of autologous bone patients become infected, 10% require replacement due to resorption and 12% become significantly resorbed, then in 32% of case the autologous bone has failed.

In each case of cranioplasty failure the patient requires readmission, a second operation to remove the bone flap, prolonged antibiotic therapy (in the case of infection), and then a new custom-made plate and readmission for a third surgical procedure.

In most cases synthetic materials such as polymethylmethacrylate and titanium mesh are used for reconstruction. Commonly reconstruction is carried out by the surgeon using such materials to sculpt the cranioplasty. More recently, hydro formed titanium plates have been used. This entails a process of CT scanning the defect, virtual reconstruction, 3D printing of moulds, pressing the plate and hand finishing. Whilst highly successful in treating more than 150 patients, the titanium cranioplasty remains in the patient for life and, as a non-biological material, presents as a preferential site for infection (approximately 5% of cases). In addition, medical CT images for assessment and treatment of neurological conditions are compromised for life due to metal artefacts arising from the plates. Furthermore, interference with metal scanning equipment commonly used for security purposes also remains a life time issue. The patients with an infected titanium cranioplasty require a fourth admission to remove the metal or polymer plate, extended antibiotic treatment and then a fifth surgical procedure to reinsert a new cranioplasty.

Mesenchymal stromal cells (MSC): MSC are multipotent adult cells capable of differentiating down multiple mesenchymal lineages. They are adherent fibroblastoid-like cells with an extensive capacity for expansion. They reside within the connective tissue of most organs and have been isolated from bone marrow, placenta, adipose tissue, umbilical cord, amniotic fluid, circulating blood, various foetal tissues, skeletal muscle synovia, dental pulp, liver, spleen, lung and dermis. Most work has focussed on MSC derived from bone marrow, however, there are also some clinical reports using adipose tissue and placental derived MSC. MSC from different sources may not be functionally equivalent or exhibit the same differentiation potential. The main functions for bone marrow derived MSC with regards to the present study is the ability to differentiate down the osteogenic lineage. It is this ability to differentiate that has seen them applied to bony non-union and the treatment of critical size bone skeletal deficits, and in particular the reconstruction of cranial voids. In the current proposal Cell and Tissue Therapies W.A. at Royal Perth Hospital have extensive experience and have applied for an TGA (Therapeutics Goods Administration, the Australian Government regulatory authority) licence to manufacture and provide MSC for patient treatment.