Biocompatibility of injectable materials

Key words in situ polymerizable biomaterials, controlled biodegradation, non-cytotoxic degradation products, environmentally responsive biomaterials. 

This chapter reviews the unique biocompatibiUty challenges presented by injectable biomaterials that are currently being investigated and developed as 

Environmentally responsive Set in situ in response to pH, temperature, or other stimulus Calcium phosphate cements (CPCs) Set in situ by an acid/base reaction 

Poly(NIPAAm) PEO-PPO block co-polymers Brushite and hydroxyapatite cements Composite CPCs incorporating a porogen 

Self-assembling Set in situ in response to phase-separation of hydrophilic and hydrophobic domains In situ polymerizable Set in situ by crosslinking of reactive monomers and macromers to form a network 

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When a synthetic material is placed in the mouth, there are many concerns. Obviously the material must be biocompatible, with an appropriate host response (Wataha, 2001). Further, the material may be subjected to mechanical stresses (shock, fatigue and abrasion), and chemical and enzymatic degradation. Thus it is important that the material is manipulated in such a way as to obtain its optimum properties to withstand the long-term rigors imposed by the oral environment. In that regard, it is advantageous to have materials that are easier to manipulate, which in turn can promote a superior outcome. This is now being achieved in some cases by the development of injectable materials. 

Soft tissue responses to biomaterials for medical devices are generally viewed from the inflammation and wound healing perspectives and are usually considered as parts of the tissue or cellular host responses to injury. Placement of a biomaterial or medical device in the soft tissue environment involves injection, insertion, or surgical implantation, all of which injure the tissues or organs involved. Early host responses are dynamic and change with time (Table 2.1). It is important to consider this time variable in determining the host response or biocompatibility of a material. 

Injectable bone substitute material consisting of CTS, citric acid, and glucose solution as the liquid phase, and tricalcium phosphate powder as the solid phase, was developed by Liu and coworkers [141]. Four types of cements have been used to investigate the mechanical properties and in vitro biocompatibility of the material. In the presence of citric acid, tricalcium phosphate partially transformed into HAp and dicalcium phosphate. 

In addition, Wang s group developed a one-step method to synthesize photo-cross-linkable macromers based on copolymers of PEG and PPE and further photopolymerized them to form hydrogels, which were capable of cell encapsulation. Qiu and co-workers have prepared a series of unsaturated PPEs (eqn [14]), which can be cross-linked. They have investigated the cross-linking, mechanical properties, degradation, and biocompatibility of these materials as injectable and biodegradable bone substitutes. 

Semi-solid bioerodible implant materials would enable the delivery of soft implants with a needle and syringe. Heller introduced such a material, poly(orthoester) IV, that shows long residence time after subconjunctival administration, an erosion-controlled drug release, and ocular biocompatibility. Depending on the ocular site of injection, the ocular lifetime of the drug ranges from 5 to 6 months. 

The IDE submission is the cmcial hurdle and major milestone that transitions a promising material into a viable and testworthy medical device. The IDE s format is a testament to this transformation. The first half of the submission is a detailed report of the injectable biomaterial s evolution and optimization -including all background data and all reports of prior investigation. This section includes the history of the material, all current mechanical and chemical testing, in vitro and in vivo modeling, and biocompatibility results. The second half of the submission, however, focuses on the injectable biomaterial as a device. This... 

The extract dilution type of cell culture assay requires a solvent extraction of the biomaterial under consideration and testing of this extract, most commonly at various dilutions, for evidence of cytotoxicity and cellular interaction. This type of cell culture assay finds its most common use in providing information for regulatory compliance. As identified in the preceding Materials for Medical Devices section and in Table 1, low-molecular-weight extractables are of concern regarding biocompatibility. The extraction assay, carried out with a series of solvents that are hydrophilic and hydrophobic, permits examination of the potential cytotoxicity of extracts and the identification of materials within a biomaterial that may be cytotoxic. These types of assays ultimately permit identification and characterization of cytotoxic materials within biomaterials or the lack of cytotoxicity, as well as providing correlation with in vivo assays such as sensitization, irritation, intracutaneous (intradermal) reactivity, and other tests where the in vivo injection of extracts is required. 

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