Patent Application
20250161352
The present invention is related to a novel use of porous calcium-based granules for promoting healing of an intra-articular or peri-articular fracture of a fractured bone.
When a fracture goes into or around a joint, it usually damages the cartilage at the ends of bones and other joint tissue. As a result, the affected joints are prone to traumatic arthritis, leading to stiffness. Repairing bone damage, maintaining joint integrity, and avoiding subchondral and metaphyseal defects caused by comminuted fractures is often a great challenge for orthopedic surgeons. Tissue engineering of synthetic bone substitutes has proven beneficial to the attachment and proliferation of bone cells, promoting the formation of mature tissues with sufficient mechanical strength and has become a promising alternative to autograft methods. An ideal bone graft substitute should present such material properties as biocompatibility, resorbability, vascularity and angiogenesis, durability, osteogenesis and osteoconduction/osteoinduction. However, in vitro and in vivo studies indicated that most of the artificial bone products in the current market, such as calcium phosphate and recombinant human bone morphogenetic protein, are poorly absorbed and uncertain in biocompatibility, even induce ectopic cartilage and bone formation or abnormal synostosis [1-6].
There is a need to promote healing of an intra-articular or peri-articular fracture of a fractured bone for early rehabilitation by preventing soft tissue adhesions and joint contractures, moreover, avoiding ectopic bone formation or abnormal synostosis.
An objective of this invention is to provide a use of porous calcium-based granules in the fabrication of a medicament for promoting healing of an intra-articular or peri-articular fracture of a fractured bone after being fixed through a surgery in a patient, wherein the porous calcium-based granules have a porosity of about 30 vol % to about 90 vol % and a granular size of about 0.1 mm to about 2.5 mm, and the porous calcium-based granules comprise calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, or a combination thereof.
Another objective of this invention is to provide a method for promoting healing of an intra-articular or peri-articular fracture of a fractured bone in a patient, comprising administering porous calcium-based granules into a joint having a fractured bone with an intra-articular or peri-articular fracture and/or administering the porous calcium-based granules to the intra-articular or peri-articular fracture of the fractured bone during or after the fractured bone being fixed through a surgery in the patient, wherein the porous calcium-based granules have a porosity of about 30 vol % to about 90 vol % and a granular size of about 0.1 mm to about 2.5 mm, and the porous calcium-based granules comprise calcium phosphate, calcium sulfate, calcium carbonate, calcium oxide, calcium hydroxide, hydroxyapatite, or a combination thereof.
Preferably, the promoting of healing of an intra-articular or peri-articular fracture of a fractured bone is free of soft tissue adhesions, joint contractures, ectopic bone formation, abnormal synostosis, or a combination thereof near the fracture bone in the patient.
Preferably, the porosity of the porous calcium-based granules is of about 60 vol % to about 80 vol %.
Preferably, the granular size the porous calcium-based granules is of about 0.5 mm to about 1.5 mm.
Preferably, pores of the porous calcium-based granules have a pore size in a range of about 30 μm to about 300 μm.
Preferably, pores of the porous calcium-based granules comprise interconnected pores.
Preferably, the porous calcium-based granules comprise calcium phosphate, calcium sulfate, hydroxyapatite or a mixture thereof.
Preferably, the porous calcium-based granules comprise a mixture of hydroxyapatite, calcium phosphate and calcium sulfate.
Preferably, the calcium phosphate is tetracalcium phosphate (TTCP), dicalcium phosphate, tricalcium phosphate, monocalcium phosphate or a mixture thereof; and the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD), anhydrous calcium sulfate, or a mixture thereof.
Preferably, the calcium phosphate is tetracalcium phosphate (TTCP), dicalcium phosphate, or a mixture thereof; and the calcium sulfate is calcium sulfate hemihydrate (CSH), calcium sulfate dihydrate (CSD), or a mixture thereof.
A synthetic, inorganic and highly porous Ca/P/S-based bone-substituting material (Ezechbone® Granule, CBS-400) was used by the doctors. CBS-400 is mainly comprised of hydroxyapatite (HA) and calcium sulfate dihydrate (CSD) with a delicate Ca/P/S atomic ratio of 54.6/39.2/6.2.
EZECHBONE® Granule is available from JOY MEDICAL DEVICES CORPORATION, 1F., No. 63, Luke 2nd Road, Luzhu District, Kaohsiung City, Taiwan. EZECHBONE® Granule has a particle size of about 0.4-1.2 mm, and a porosity of about 70-80 vol %, and is TTCP/DCPA/CSH-derived porous granules prepared based on the method disclosed in U.S. Pat. No. 8,784,551. The porous granules of calcium compound can be prepared from a mixed powers of TTCP/DCP/calcium sulfate (preferably TTCP/DCPA/CSH; more preferably TTCP/DCPA/CSH/CSD) and a pore forming agent, which is then mixed with a NH4+ solution to form a paste. The paste is hardened into a block in a mold, followed by washing the pore forming agent from the hardened block and breaking the block into porous granules; or breaking the block prior to washing. The porous granules are composed of hydroxyapatite, calcium sulfate (primarily CSD), and less significantly unreacted TTCP, DCP, and CSH. (DCPA: dicalcium phosphate anhydrous).
According to the operation notes from the medical records, we collected fourteen cases of complex intra- and peri-articular fractures with Ezechbone® Granule bone grafting between 2019/11 and 2021/11. We studied the evidence of bone healing by reviewing, interpreting and analyzing the medical image recordings. All imaging images were reviewed, discussed and interpreted by an orthopedic surgeon with 15+ years of clinical experience in the field along with a diagnostic radiologist with 20+ years of experience. As indicated in X-ray, the initial bone graft area had turned into a nidus-like appearance (
From November 2019 to November 2021, we followed 14 cases (Table 1), including 11 males and 3 females, with an average of 34.1±9.8 y/o. The fracture types applying bone graft substitutes included 6 peri-articular and 8 intra-articular fractures. The surgical sites were located in two olecranons, two in the distal radius, two at the base of the proximal phalanx, four in the scaphoid, one in the radial head, and three in the metacarpal bones individually. According to medical image interpretation of X-rays, the time to nidus-like formation after bone grafting was 2.3±0.5 weeks; the time to initial callus formation was 4.7±1.0 weeks; and the time to good healing was 10.3±1.3 weeks. In four of the 14 cases, the bone substitute material was scattered in the soft tissue around the bone graft area and around the adjacent joint due to the treatment process (
It is generally recognized that, in clinical orthopedics, the treatment of complicated fracture, bone defects, delay- or non-union is a challenging and difficult issue. The bone substitute used in the present study (Ezechbone® Granule CBS-400) was observed to quickly integrate into surrounding bone within three weeks after grafting, while the initial callus formation of calcified deposits could be found within six weeks, indicating the early stage of repair. To the end of the follow-up, all of these cases healed entirely within three months. In addition, the CBS-400-derived earlier callus formation in the early stage of repair made it possible for us to shorten the start time of rehabilitation from 4-6 weeks after surgery to within 3 weeks. As a result, the patient may return to daily life function after 3.5 months of follow-up and rehabilitation treatment.
