Papers by Author: Aliassghar Tofighi

Abstract: The first generation of synthetic bone substitute materials, hydroxyapatite (or HA), was initially investigated as a “non self-hardening” biomaterial for remodeling of bone defects. CPBCs concepts were used as a platform to initiate a second generation of injectable, self-hardening cement. The variety of CPBC’s chemical composition leads to a better understanding of their mechanism of reaction and their proposed classification: acid-base, mono-component and hydrolysable. After hydration, mixing, and full chemical reaction, these cements have the ability to precipitate different end products (e.g. HA, calcium deficient apatite, carbonated apatite, brushite, etc.). In fact, the initial idea of having higher mechanical performance (>50 MPa in compression) for a bone void filler application was abandoned and has led to a greater focus on cement fast-hardening (<15 min), higher total porosity (>60%), extended performance of injectability (8 to 22 G), fast resorbability (< 2 years) and user-friendliness for the clinicians. A new CPBC combination (cement plus additives) has particularly improved rheological and biointegrity performance. A hybrid of CPBC-DBM (Demineralized Bone Matrix) has also added an osteoinductivity performance to the initial osteoconductive CPBC.This paper will propose a comparison of the chemical composition, reaction, and performance characteristics of major commercially available CPBC products. Furthermore, it will describe today’s surgeon’s CPBC needs as bone substitute materials for different clinical applications. Finally, we will discuss what we learned so far, how we can resolve several clinical impacts & product recall, and how we believe CPBC designers can meet development challenges, and users’ specific requirements.

Abstract: A new class of osteoconductive and osteoinductive combination biomaterials composed of calcium phosphate cement (CPC), demineralized bone matrix (DBM) and a water-soluble viscosity modifier were prepared and characterized in-vitro and in-vivo. In previous studies, a range of combinations formulations were tested in order to compare their performance characteristic. In-vitro characterization results show that the mechanical strength is decreased when the amount of DBM increases. However, DBM does not affect the CPC’s ability to set hard and convert to nanocrystalline apatitic calcium phosphate, which shares the chemical structure of natural bone as seen in x-ray diffraction. It is known that the DBM alone is osteoinductive. In-vivo osteoinductivity testing of the formulations in an intramuscular, athymic rat model demonstrated that the combination material is also osteoinductive. Two formulations were chosen for in-vivo efficacy testing based on the results of in-vitro and in-vivo characterization. These formulations were studied using rabbit critical-sized femoral core defect model. The formulations were composed of DBM with particle sizes of 250 to 710 μm, carboxymethyl-cellulose (CMC) as the viscosity modifier and weight percent compositions of 50% DBM/ 45% CPC/ 5% CMC and 60% DBM/ 30% CPC/ 10% CMC. Bone integration and healing was graded at 6, 12, and 24 weeks. The two formulations were compared to the gold standard autograft at 12 weeks and to an empty defect as the negative control at 24 weeks. Based on micro-computed topography (μCT), both formulations allowed for continuity of bone throughout the defect region at all time points. No differences in dense area fraction were seen between two formulations at 6 weeks (p = 0.8661). There was no significant statistical difference between the two formulations and autograft at 12 weeks (p = 0.2467). At 24 weeks, both formulations had significantly higher dense area fractions than empty controls (p = 0.0001). Histologically, the biology of the treatment areas appeared to have returned to normal by 24 weeks with CPC appearing to be the principal osteogenic inducer. In conclusion, these combinations of CPC and DBM offers significant advantages (handling, mechanical properties and osteoinductivity) over current DBM products and can be an effective alternative to autograft in healing of bone defects.

Abstract: Alpha-bsm® is a first generation self-setting, injectable and moldable apatitic calcium phosphate cement (CPC) based on amorphous calcium phosphate (ACP). ACP was prepared using low temperature double decomposition technique, from a calcium solution (0.16 M), and phosphate solution (0.26 M) in a basic (pH~13) media. ACP was than stabilized using three crystal growth inhibitors (CO32-, Mg2+, P2O74-), freeze-dried, and heated (450 °C, 1h) to remove additional moisture and some inhibitors. Dicalcium phosphate dehydrate (DCPD) was also prepared using wet chemistry at room temperature from calcium and phosphate solution, respectively, 0.3 M and 0.15 M. ACP and DCPD powder were combined at a 1:1 ratio and ground to produce Alpha-bsm® bone cement. The cement is supplied as a powder and when mixed with an appropriate amount (0.8 ml/g) of physiological saline at room temperature, forms an injectable putty-like paste. The paste has a working time of about 45 minutes at room temperature, when stored in a moist environment. The setting reaction proceeds isothermically at body temperature (37°C) in less than 20 minutes, forming a hardened, porous (total porosity 50 to 60%), low crystalline (40% comparing with HA), apatitic calcium phosphate cement with a compressive strength range of 10 to 12 MPa. Extensive pre-clinical studies (rabbit radius critical sized defect, canine tibia osteotomy, sheep tibia, primate fibula fracture healing, and primate fibula critical size defect) demonstrate that Alpha-bsm® undergoes remodeling in conjunction with new bone formation. The next generation of Bone Substitute Materials (Beta-bsmTM and Gamma-bsm TM) are formulated based on the Alpha-bsm® chemistry but differ in powder processing (e.g. milling) technique. These materials are also self-setting, injectable and/or moldable apatitic calcium phosphate cements with improved handling and mechanical properties. The setting & hardening reaction of these new CPCs proceeds isothermically in less than 5 minutes at 37°C and once hardened demonstrate a compressive strength of 30 to 50 MPa. The final product (after full conversion) is a low crystalline (40% compared with Hydroxyapatite), calcium deficient (Ca/P atomic ratio = 1.45) carbonated apatite similar to the composition and structure of natural bone mineral (crystal size: length = 26 nm, width thickness = 8 nm). A desirable feature of these cements is their high surface chemistry (with specific surface area of about 180-200 m2/g) which is ideal for remodeling and controlled release of growth factors. A pilot rabbit critically sized femoral defect study comparing the three synthetic family products demonstrate that they share similar remodeling and resorption characteristics up to 52 weeks. Physico-chemical and mechanical performance of these next generation CPCs are favorable when compared with existing CPCs in the market, specifically material working time (at room temperature), cohesivity in a wet environment and fast setting & hardening rate (at body temperature).

Abstract: Single-component, self-setting and injectable calcium phosphate cement (CPC) based on amorphization process of dicalcium phosphate dehydrate (DCPD) is proposed. After preparation of DCPD by wet chemistry, the material was dry milled in an Attritor high energy process (at 400 RPM) during 20 minutes. Experiments were also conducted using a regular ball milling process at 15 and 30h residence time. Amorphization of DCPD confirmed using FTIR, XRD and 31 P solid-states NMR (cross-polarization and decoupling). Upon hydration of amorphized DCPD powder with saline (0.55 ml/g), putty-like consistency produced. The paste hardened in 30 minutes at 37°C and reached a compressive strength of about 20 MPa. The final product was a low crystalline calcium deficient apatite, similar to the composition and structure of bone mineral.

Abstract: The first generation of synthetic bone substitute materials (BSM) was initially investigated in the mid 1970s using hydroxyapatite (HA) as a biomaterial for remodeling of bone defects. The concepts established by CPC pioneers in the early 1980s were used as a platform to initiate a second generation of BSM for commercialization. Since then, advances have been made in composition, performance and manufacturing. A self-setting and injectable calcium phosphate cement (CPC) based on amorphous calcium phosphate (ACP) with calcium to phosphate (Ca/P) atomic ratio less than 1.5, combined with dicalcium phosphate dihydrate (DCPD or brushite, seeded with apatite), is proposed. Amorphization of raw material was observed following high energy mechano-chemical processing. Upon hydration, the cement hardened in less than 3 minutes at 37°C and reached a maximum compressive strength of about 50 MPa. The final product was a low crystalline calcium deficient carbonated apatite similar to the composition and structure of bone mineral. In vivo performance of this cement in mediating bone healing was compared to α-BSM® in a rabbit femoral defect model. Performance characteristics of some commercially available CPC products are compared. The concerns of CPC designers and the needs of product users (surgeons) are discussed.

Abstract: Low crystalline apatite (LCA) and calcium phosphate cements (CPC) based on amorphous calcium phosphate and dicalcium phosphate dihydrate (1 to 1 ratio) were combined with bioresorbable PLGA copolymer (0 to 20 wt.%) for preparation of solid-formed devices. A pilot manufacturing based on powder processing techniques using isostatic pressure (44,000 psig) was conducted. Processing parameters such as isostatic pressure, temperature, times and device dimension were varied to achieve appropriate mechanical properties comparable to that of allograft bone dowel used as a gold standard in clinical application. The solid-form devices were characterized for physico-chemical and mechanical performance, as well as subjected to an in-vitro wet environment incubation at body temperature (37°C). Fluid diffusion was investigated to evaluate the fluid absorption (through microporosity) and the compressive strength of wet devices vs. incubation time (up to 30 days) was also studied. The shear strength and compressive strength of pure LCA dowels was respectively 26 and 122 MPa, which corresponds to a process densification of about 30%. The compressive strength was dramatically improved with addition of various amounts of copolymer. The maximum compressive strength of 180 MPa was obtained for dowels containing 10 wt.% copolymer. Calcium phosphate composite also increased the shear strength to about 42 MPa. These mechanical performances were significantly higher than that of allograft bone dowel (MD-II™), reported about 10 MPa. A pilot sheep interbody fusion of lumbar spine (L3/L4 and L4/L5) demonstrates mechanical integrity and intervertebral fusion at 6 months. LCA was found to be the most suitable CaP material because of its biocompatibility, chemical composition, nano-structure and high specific surface area that exhibits in-vivo biointegrity and cell mediated process.

Abstract: ACP (amorphous calcium phosphate) and DCPD (dicalcium phosphate dihydrate, or Brushite) powders were high energy dry ball milled at a 1:1 ratio for 1, 2, 3, 4, 10, or 24 hours to produce a variety of powders for use as calcium phosphate cements (CPC). A 1:1 blend of powders not subjected to milling was used as baseline material (control). Physicochemical and mechanical characterization was performed on the powder or cement at each milling time point and compared to control. The following changes were noted after 24 hours of milling: the crystallinity was reduced to a fully amorphous phase, the tap density increased by 89%, the specific surface area decreased by a factor of 7, and the total porosity of hardened cement decreased by 50%. Additionally, the compressive strength of hardened CPC increased from 2.6 MPa to a peak of 50 MPa after 10-h milling. The rate of paste hardening increased throughout the 24-h period. Full conversion of each milled material produced a similar composition low-crystalline calcium deficiency apatite with Ca/P atomic ratio of 1.45 and specific surface area around 195 m2/g. The specific structure of these CPC, with high surface area and reactivity of nano-crystals, is ideal for in vivo remodeling of new bone and controlled release of protein and growth factors.