TECHNICAL FIELD OF INVENTION

The present invention relates to development of a porous implant type which eventually melts off and replaced with new leaves growing tissue to cover craniofacial defects in the body and shaping of the same with rapid prototyping and lyophilization methods.

BACKGROUND OF INVENTION

The result of craniofacial bone reconstruction is considered to be dependent on surgical skills, quality of adjacent soft tissues, size and location of the bone defect and choice of repair method. The methods include free and vascularized bone grafts, a variety of biomaterials and, more recently, the use of osteoinductive growth factors. The use of autologous bone for craniofacial reconstruction may be restricted due to limited amounts of donor bone. The need of remodelling the harvested bone into complex shapes may also complicate the surgery. In addition, significant bone resorption using free bone grafts and the enhanced morbidity and risks from harvesting bone grafts cannot be disregarded.

Ideally, their role in reconstructive procedures are not only simply replacing the missing bone part, but also stimulate osteoconduction by acting as a scaffold for bone re-growth. Implantable materials need to fulfil the demands on biocompatibility with no or low side effects, including infiltration of leucocytes and fibrosis.

Currently the craniofacial implants are metallic, non biodegradable materials and the target is to develop highly porous, biodegradable implant materials that will erode in time and be replaced by the newly developing tissue. There currently are polymeric, biodegradable implants but they are not porous and therefore tissue ingrowth into the implant and integration is lower than implants with porous implants. Moreover, the current craniofacial implants do not carry growth ^' enhancing compounds (e.g. growth factors) and antimicrobial compounds.

Despite numerous examples of the use of synthetic, permanent implant materials from metals such as titanium, or degradable and nondegradable polymeric materials such as acrylic polymers, such as polymethylmethacrylate (PMMA), or polyesters, polyethylene (PE) and polyethylether ketone (PEEK), in the reconstruction of traumatic, developmental and surgical osseous defects the healing has not been as needed. Bone autograft is the golden standard as the implant material for repairing bone defects, simply because the risk of rejection and related immunological problems are minimal. However, the amount of autogenous bone available for transplantation is limited since it has to be harvested from the patient's own body which might be limited or unsatisfactory quality. Besides, harvesting involves postoperative complication risks, and the pain. Rapid and extensive supply of appropriate nutrient is essential and rapid vascularization is the best way to achieve this. Another complication is that several years may be required for reabsorption of allograft while the new bone is formed. As a consequence, the search for suitable alternatives to host and donor bones is intensive.

The ideal biomaterial for maxillofacial and other types of bony reconstruction has to be biocompatible, capable of allowing tissue in-growth and provide a framework for cell adhesion and guidance during new bone development. The material needs to be malleable or processable, serve as a carrier medium for osteogenic proteins. A high initial stiffness would allow proper attachment of the defect edges or fit the defect site perfectly with sufficient strength to mimic the cranial bony tissue. This will need to be gradually resorbed and the stiffness decreased in parallel with the strength of the healing bone taking over the deficiency created by the resorbing implant.

The present invention discloses a craniofacial implant material composition and also about the production approach. There are several patent documents disclosing similar invention and theses are listed as follows:

• US 2009 060969 Al: This document protects a biocompatible and porous implant which is used in transplantation, craniofacial and ortopedical surgery.

• US 2004 258732 Al: This patent is about a biodegradable and organic-inorganic porous implant that involves bioceramic powder.

• KR 2010 01022753 A: This document discloses an implant that involves a metal cage.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Sponge type implant.

Figure 2. Patient specific implant. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to defining biocompatible, biodegradable composite compositions, and the production and/or preparation of biomedical craniofacial implants that would be used in closing cracks or filling gaps in skull of patients with porous and biodegradable polymeric materials. The production of two different types of implants with designed or random pore sizes and pore size distribution are prepared by two different methods:

1. Rapid prototyping or additive manufacturing

2. Lyophilization.

Some bioactive agents like antibiotics, growth factors are added into these implants. Besides with the added antibiotics, the implants will be freer of infection and with the growth factors their integration will be better. Since there will be no need for revisions surgeries, no risks due to new surgery, trauma of the procedure; the pain and the cost of the surgical procedure will be avoided. Under optimum circumstances, patients' own osteoblasts or bone marrow are added to the porous implant to obtain a tissue engineering product.

Ideally the implant material should be easily processed into various craniofacial components such as screws and plates. Since a metallic implant will not grow with the patient, a biodegradable material that would induce cell growth into the implant and gradually will go away is what is needed. Thus, a certain level of porosity is needed. Depending on the defect type this porosity is between 70 to 90%. Typical pore size range is ca. 100-300 urn, because otherwise cells do not properly fill the gaps of the implant.

The use of computerized tomography (CT) scan of patient's defective tissue allows the production of patient specific implants for defects with highly irregular contours using rapid prototyping or more generally, additive manufacturing, approaches. The polymers to be used in rapid prototyping are selected based on their chemical and mechanical properties such as melting temperature, molecular weight, hydrophilicity, presence of cell adhesive groups or moieties in addition to their rate of degradation in this invention. The ability to vary the degradation rate of biocompatible relatively short length polyesters such as polylactide (PLA) and polyglycolide (PGA) by copolymerization or blending in addition to their FDA (fused deposition modeling) approval has made these materials a natural choice for bone repair. Another polyester that has a potential is poly(E-caprolactone) (PCL) which has a lower T _m (60° C) which makes it a more easily processable material, suitable for additive manufacturing. Moreover, polymers such as PLGA, PLLA or PHBV are suitable as implant materials.

Another approach is to use lyophilization (freeze drying) that produces less controlled pore sizes and porosity, unlike additive manufacturing where the pore sizes and porosity can be very accurately controlled. However, freeze drying produces much higher porosity materials, because the wall thickness of the spongy structures are much lower than the fibers used in additive manufacturing (several tens or hundreds of microns vs several micrometers or nanometers.

In addition, to enhance healing, sterility and the mechanical properties of the implants, the composition of the implant material is also modified according to the needs. The candidate molecule groups to fulfil these functions are growth factors, antibiotics and minerals with chemistries similar to bone mineral component.

Experimental

1. Sponge type implant

In this method; PCL (or another polyester such as poly(L-lactide), PLGA, PHBV) is dissolved in chloroform or dichloromethane to produce a 5-10% w/v solution. Then the solution is frozen at -20°C of the freezer compartment of the refrigerator or at the deep freeze at -80°C until completely solid (overnight). The solid polymer solution is then taken to a lyophilizer and allowed to dry under vacuum in frozen state. The resultant sponge is the highly porous implant material without any bioactive agent.

l.i. In order to incorporate mineral/ceramic components such as hydroxyapatite, tricalcium phosphate or zeolite, or antibiotics, or growth factors, they are suspended in the initial polymer solution at a concentration of up to 40%(w/w) with respect to the polymer. Upon lyophilization the minerals, or the bioactive agents are entrapped with the walls of the sponge. They will release their content gradually with a rate depending on the degradation and hydration rate of the polymer (controlled by polymer crystallinity, molecular weight and chemistry) and function by increasing cell integration into the pores.

l.i.i. Another approach to incorporation of the bioactive agents onto the sponge the sponge is exposed to oxygen plasma at 13.56 Hz 5-10 Watts for 15 s to 10 min. Onto this activated surface, an aqueous solution of the bioactive agent (5-20% (w/v) depending on the viscosity of the solution) is applied immediately so that the radicals created on the sponge surface are not deactivated by the medium. After drying under vacuum or air drying the sponge is ready to use.

l.i.i.i. Another approach to incorporation of bioactive agents into the sponge structure is to place zeolite in an aqueous solution of the bioactive agent (5-20% w/v depending on the viscosity of the solution) and then apply vacuum-air cycles to remove the air within the pores of the zeolite and replace them with the drug solution. Then the method l.i. is applied. Upon drying the bioactive agent loaded zeolite is incorporated into the sponge walls as was explained above.

2. Patient Specific Implant

Patient specific implant is prepared by using the MR or CT image of the defect site and then feeding this information to a rapid prototyping device that extrudes a polymeric material upon application of heat and pressure. The product is in the form of fibers that have a geometry based on the computer mode selected to fill the contours defined by the CT image. These could be in the form of grids the organization of different layers with respect to each other could be varied depending on the porosity needed. With this approach a solid polymeric device is obtained upon cooling of the extruded polymer.

2.i. Its loading with bioactive agents and the ceramics/minerals is achieved by mixing the these materials with the polymer and then extruding them together with the polymer in the form of fibers.

2.Ϊ.Ϊ. If heat is detrimental for the bioactivity of the ingredients then the construct is made by extrusion through rapid prototyping as above and then approach l.i.i. is applied to coat the bioactive agents on the surface of the construct.