US-12616775-B2 - Method for manufacturing bone-regeneration material comprising biodegradable fibers by using electrospinning method

US12616775B2US 12616775 B2US12616775 B2US 12616775B2US-12616775-B2

Abstract

A bone-regeneration material comprising a biodegradable fiber produced using an electrospinning process, wherein the biodegradable fiber comprises 30 to 50 wt % of PLLGA resin and 70 to 50 wt % of β-TCP fine particles substantially uniformly dispersed in the PLLGA resin without forming aggregates, wherein the β-TCP fine particles are not chemically bonded to the PLLGA resin, and surroundings of the β-TCP fine particles are covered by the PLLGA resin so that the β-TCP fine particles are not separated from the biodegradable fiber during a formation of the fiber, and wherein the bone-regeneration material is sterilized by using radiation sterilization with gamma ray.

Inventors

Toshihiro Kasuga
Yasutoshi Nishikawa

Assignees

NATIONAL UNIVERSITY CORPORATION NAGOYA INSTITUTE OF TECHNOLOGY
ORTHOREBIRTH CO., LTD.

Dates

Publication Date: 20260505
Application Date: 20240409
Priority Date: 20160428

Claims (6)

1 . A bone-regeneration material comprising a biodegradable fiber produced using an electrospinning process, wherein the biodegradable fiber comprises 30 to 50 wt % of a copolymer of poly-L-lactic acid and polyglycolic acid (PLLGA) resin and 70 to 50 wt % of phase tricalcium phosphate (β-TCP) fine particles substantially uniformly dispersed in the PLLGA resin without forming aggregates, wherein the β-TCP fine particles are not chemically bonded to the PLLGA resin, and surroundings of the β-TCP fine particles are covered by the PLLGA resin so that the β-TCP fine particles are not separated from the biodegradable fiber during a formation of the fiber, and wherein the bone-regeneration material is has been sterilized by gamma radiation.
2 . The bone-regeneration material of claim 1 , wherein a weight ratio of lactic acid and glycolic acid in the PLLGA resin is approximately 85-50:15-50.
3 . The bone-regeneration material of claim 1 , wherein outer diameters of the β-TCP fine particles are in a range of 0.5 μm to 4 μm.
4 . The bone-regeneration material of claim 1 , wherein an outer diameter of the biodegradable fiber is 10 μm to 250 μm.
5 . The bone-regeneration material of claim 1 , wherein the bone-regeneration material formed of the biodegradable fiber is in a cotton-wool form having a bulk density of 0.01 to 0.1 g/cm 3 .
6 . The bone-regeneration material of claim 1 , wherein a molecular weight of the PLLGA resin is 60,000 to 600,000.

Description

CROSS REFERENCE TOP RELATED APPLICATIONS This is a continuation application of U.S. application Ser. No. 16/840,309, filed on Apr. 3, 2020, which is a continuation of U.S. application Ser. No. 15/773,554, filed on May 3, 2018, which is a national stage application of PCT/JP2017/016931, filed on Apr. 28, 2017, which claims the priority of Japanese Application No. 2016-091118, filed on Apr. 28, 2016. The disclosures of these prior applications are incorporated by reference in their entirety. TECHNICAL FIELD This invention relates to a method for producing a bone-regeneration material comprising biodegradable fibers by using an electrospinning method. BACKGROUND Methods being practiced in the field of bone regeneration therapy involve implanting into a bone defect part a bone regeneration material prepared by adding a bone morphogenetic factor into a matrix resin made of a biodegradable resin such as polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA) are performed. Since, after the implantation of the bone regeneration material in the body, the material is in contact with body fluid and degraded and thereby the bone morphogenetic factor contained in the material is slowly release and also the material is absorbed and removed by the body over time, an effective bone formation is achieved with a little burden on the patient. The requirement for a bone-regeneration material to exhibit an osteogenic activity when it is implanted in the body is that a matrix resin therein serves as a scaffold and is a resin on which a bone morphogenetic factor can be supported. As a bone morphogenetic factor, calcium phosphate, in particular, β phase tricalcium phosphate (β-TCP) is preferably used since it has an excellent osteogenic activity. Since the bone resorption and/or replacement by β-TCP requires several months, it is desirable that the matrix resin comes in contact with body fluid and hydrolyzed early to start controlled release of calcium phosphate, continues the controlled release for a certain period of time, and then is rapidly degraded and absorbed to be disappeared. Recently, biodegradable fiber containing a bone morphogenetic factor has been actively used as a bone-regeneration material, and electrospinning processes are used as a method for producing such biodegradable fiber. In the electrospinning process, a spinning solution is ejected as a thin fiber from a nozzle and pulled by the electrostatic attraction in the electric field to be deposited on a collector. Therefore, it is an important object to prepare a spinning solution that is available for such spinning. In vivo and in vitro evaluation of flexible, cottonwool-like nanocomposite as bone substitute material for complex defects Acta Biomaterialia 5 2009 discloses formation of fibers in a cottonwool-like form using a low temperature electrospinning process from a spinning solution. The spinning solution is prepared by adding PLGA to a solvent and dissolved in the solvent in which amorphous TCP fine particles are dispersed. The method of the document involves preparing a spinning solution (the weight ratio of PLGA/TCP is 60/40) for electrospinning by dispersing TCP particles by sonication in chloroform, providing PLGA to and dissolved in the chloroform, and stirring the mixture. The inventors of the present invention proposed a method of preparing a spinning solution in which a composite is prepared by adding silicon-releasing calcium carbonate particles together with calcium phosphate particles to a PLA melt and mixing and kneading and cooling and solidifying the mixture. The composite is then dissolved by using a solvent to produce a spinning solution (Japanese patent No. 5855783). According to this method, a spinning solution can be produced by incorporating 50% by weight or more inorganic particles into a polylactic resin. However, since the degradation and absorption of PLA in the body is slow, the possibility has been pointed out that it prevents inorganic fine particles from early exhibition of osteogenic potential. Moreover, there is the problem that when fine particle powder with a particle size of about 1 to 4μ is provided to and kneaded with a solution which has been heated to above the melting point of the PLA resin and melted, the fine particles are aggregated and fail to be completely dispersed in the resin by kneading. CITATION LIST Patent Literature Patent Literature 1: Japanese Patent No. 5855783 Non Patent Literature Non Patent Literature 1: In vivo and in vitro evaluation of flexible, cottonwool-like nanocomposite as bone substitute material for complex defects, Acta Biomaterialia 5, 2009, 1775-1784, Stark et al., University of Zurich. SUMMARY OF INVENTION Problem to be Solved by the Invention PLGA is superior to PLA in that it is hydrolyzed at a high speed and the resin is degraded and absorbed when implanted in the living body allowing controlled release of a bone morphogenetic factor early without remaining in the bod