Patent Publication Number: US-2012046622-A1

Title: Method and apparatus for making a porous biodegradeable medical implant device

Description:
TECHNICAL FIELD 
     This application relates generally to medical devices and more particularly to a method and apparatus for forming a porous medical device. 
     Background 
     Porous medical devices can be useful as implants for tissue regeneration and drug delivery, especially in nerve rehabilitation applications. Unfortunately, it is particularly challenging to provide such medical devices with one or more lumens in a manner suitable for mass production. There is therefore a need for methods and apparatus to enable easier mass production of such medical devices, so that the cost of healthcare to patients can be better managed. 
     SUMMARY 
     According to a first exemplary aspect, there is provided a method of producing a porous biodegradable medical implant device, the method comprising providing a mixed blend comprising a mixture of at least two biocompatible materials having different degradation or solubility characteristics; molding the mixed blend to produce a molded part; and processing the molded part to remove one of the at least two biocompatible materials by a predetermined amount from the molded part to produce the porous biodegradable medical implant device. 
     The providing step may include compounding the at least two biocompatible materials to form the mixed blend. 
     The compounding may include mixing the at least two biocompatible materials with a medicinal product or additives to form the mixed blend. 
     One of the at least two biocompatible materials may be a water soluble polymer and another of the at least two biocompatible materials may be a water insoluble polymer. 
     The blend may contain 10 to 20 wt % of the water soluble polymer. 
     One the at least two biocompatible materials may be selected from the group consisting of PEG, water soluble triblock copolymer of polyethylene oxide) and poly(propylene oxide), water soluble diblock copolymer of poly(ethylene oxide) and poly(propylene oxide), water soluble poly(propylene oxide), polyvinylpyrrolidone, and polyacrylamide. 
     Another of the at least two biocompatible materials may be selected from the group consisting of PCL, PCL-PEG block copolymer, PCL-polysiloxane block copolymer, other PCL block copolymers with melting temperatures lower than a threshold temperature, poly(lactic-co-glycolic acid), poly(hydroxybutyrate), and other polyesters and polyester copolymers with a melting temperature lower than a threshold temperature. 
     The threshold temperature may be about 85° C. 
     The compounding may be performed at a compounding temperature of between 65° C. and 85° C. 
     The compounding temperature may be about 80° C. 
     The molding may include molding the mixed blend at a molding temperature of below 85° C. to produce the molded part. 
     The molding temperature may be between 65° C. and 85° C. 
     The molding step may include increasing a length of a mold cavity during injection of the blend into the mold clay. 
     The processing step may include immersing the molded part in water to remove the predetermined amount of the one of the at least two biocompatible materials to form a leached part. The immersing may be performed at a temperature of around 25° C. to 40° C. for 6 to 12 hours. Alternatively, the immersing may be performed for up to two days. 
     The method may further comprise a step of freezing the leached part to remove excessive solvent from the leached part to form the porous biodegradable medical implant device. 
     According to a second exemplary aspect, there is provided an apparatus for forming a molded part for producing a porous biodegradable medical implant device, the apparatus having an interchangeable mold component which includes a first mold component having an elongate hollow body; and a second mold component having an elongate body extending from the first mold component to partially define a cavity for receiving a mixed blend to be molded to produce the molded part, the second mold component being arranged to be retractable within and configured to cooperate with the elongate hollow body of the first mold component. 
     The first mold component may be further configured to move relative to the second mold component for increasing a length of the mold cavity during injection of the mixed blend into the mold cavity. 
     The first mold component may be configured to move relative to the second mold component to push the molded part off the second mold component after solidification of the molded part around the second mold component in the mold cavity. 
     The second mold component may comprise a plurality of longitudinally extending micro grooves. 
     The second mold component may be configured to form at least one through hole in the molded part along a longitudinal axis of the first mold component. 
     According to a third exemplary aspect, there is provided a porous biodegradable medical implant device comprising a cylindrical tube having a porous and biodegradable structure and at least one elongate channel disposed therein along a longitudinal axis of the device. 
     The at least one elongate channel may include an inner surface having a plurality of longitudinally extending micro grooves formed thereon. 
     The porous biodegradable medical implant device may further comprise at least one drug loaded therein for gradual release of the drug during degradation of the device. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a flowchart part illustrating an exemplary embodiment of a method of forming a medical device. 
         FIG. 2A  is a cross-sectional view of an exemplary embodiment of an apparatus for forming a medical device according to the method of  FIG. 1 ; 
         FIG. 2B  is the apparatus of  FIG. 2A  in an alternative molding configuration; 
         FIG. 3A  is a schematic drawing of an exemplary embodiment of the interchangeable mold components of  FIG. 2 ; 
         FIGS. 3B and 3C  are schematic drawings of the interchangeable mold components of  FIG. 3A  with one embodiment of a part of  FIG. 1 . 
         FIG. 4A  is an enlarged schematic drawing of the embodiment of the interchangeable mold components of  FIG. 3A ; 
         FIG. 4B  is an enlarged schematic drawing of the part of  FIGS. 3B and 3C . 
         FIG. 5A  is a perspective view of an exemplary embodiment of a medical device formable using the method of  FIG. 1 ; 
         FIG. 5B  is a microscopic image showing a porous structure of the medical device of  FIG. 5A ; 
         FIG. 5C  is a cross-sectional view of the medical device of  FIG. 5A . 
         FIG. 6A  is a schematic drawing of an exemplary embodiment of the interchangeable mold components of  FIG. 2 ; 
         FIG. 6B  is a schematic drawing of an exemplary embodiment of a part formable using the interchangeable mold components of  FIG. 6A . 
     
    
    
     DETAILED DESCRIPTION 
     An exemplary embodiment of a method  100  of making a porous biodegradable medical implant device  700  and an exemplary apparatus  200  for making the device  700  will be described with reference to  FIGS. 1 to 6B  below. 
     A selecting step  102  of the method  100  includes selecting at least two biocompatible materials characterized by different solubility in a predetermined solvent or -different rates of degradation. Selecting the at least two biocompatible materials may comprise selecting at least one biocompatible first material and at least one biocompatible second material, wherein the at least one biocompatible first material is less soluble in a predetermined solvent than the at least one biocompatible second material, and wherein the at least one first material is also degradable under physiological conditions. Being under physiological conditions refers generally to being implanted or introduced in whole or in part into the body of a living organism such as a human body. 
     The selecting step  102  further includes selecting a threshold temperature. The threshold temperature is selected to be higher than the melting point of the selected materials, and lower than a temperature above which chemical reactions may occur between the selected materials. The threshold temperature is selected to be lower than a temperature above which at least one of the selected materials will be rendered unsuitable for implantation or introduction in whole or in part into a living organism such as a human being. 
     The at least one biocompatible first material is selected from a first group consisting of: polyethylene glycol (PEG), water-soluble triblock copolymer of poly(ethylene oxide) and poly(propylene oxide), water-soluble diblock copolymer of poly(ethylene oxide) and poly(propylene oxide), water soluble poly(propylene oxide), polyvinylpyrrolidone, and polyacrylamide. 
     The at least one biocompatible second material has a different solubility in water from the first biocompatible material, and is selected from a second group consisting of: poly(caprolactone) (PCL), PCL-PEG block copolymer, PCL-polysiloxane block copolymer, poly(lactic-co-glycolic acid), and poly(hydroxybutyrate). The at least one first material and the at least one second material are selected such that they do not chemically react with one another below the selected threshold temperature. The selected at least two biocompatible materials are selected to be chemically inert to one another, that is to say, there will not be chemical reaction between the selected materials under the threshold temperature. It will be understood by one skilled in the molded part that physical interactions, such as any formation of van der Waals bonds between the selected materials, do not constitute chemical reactions. 
     The method  100  further includes a step  104  of compounding all the materials selected at selecting step  102 . The step  104  of compounding involves mixing all the selected at least two biocompatible materials at a compounding temperature that is below the selected threshold temperature and above the melting temperatures of the selected at least two biocompatible materials. Accordingly, the step  104  of compounding, does not involve chemical reactions between the selected materials since it is performed at a temperature below the selected threshold temperature. The step of  104  of compounding is thus a step of physically forming a polymeric mixed blend or mixture of the selected at least two biocompauble materials without chemically reacting any of the materials in the mixed blend. This is necessary in order to retain the distinct solubility characteristics of each of the at least two biocompatible materials, so as to allow one of the at least two biocompatible materials to be subsequently remove in order to form pores in the device  700 . 
     In an exemplary embodiment, water is selected as the predetermined solvent. PEG and PCL are selected as the biocompatible first and second materials respectively. PEG is a biocompatible material that is relatively more soluble in water when compared to PCL. PEG may be chemically or physically cross-linked, and is relatively more soluble in water compared to PCL. PCL is a biocompatible polyester that may be degraded by hydrolysis of its ester linkages under physiological conditions. The PEG has a melting point of 50° C. and the PCL has a melting point of 60° C. Below 85° C., the two materials do not undergo chemical reactions or become unsuitable for incorporation with the human body. Thus, in the exemplary embodiment, the selected threshold temperature is 85° C. 
     In the exemplary embodiment, the polymeric mixed blend resulting from the compounding step  104  contains 10 to 20 wt % of PEG. The compounding temperature is about 80° C. In other examples, the compounding temperature may range from about 65° C. to about 85° C. It is also envisaged that the compounding temperature may be between 67° C., and 83° C., 70° C. and 80° C. 72° C. and 78° C. etc. 
     After the compounding step  104 , the method  100  further comprises a molding step  108  configured to form a molded part  500  using the mixed blend. 
       FIG. 2A  shows a preferred embodiment of the apparatus  200  configured to carry out the molding step  108  of the method  100 . The apparatus  200  is configured for use with an injection molding machine. The apparatus  200  includes a stationary mold component  210  having a conduit or sprue  212  configured to direct and convey a melt  600  to a mold cavity  214 . The melt  600  is formed by subjecting a predetermined amount of the mixed blend to a molding temperature that is above the melting point of the mixed blend and below the threshold temperature, thereby ensuring that the distinct solubility characteristics of each of the at least two biocompatible materials are retained after molding  108 . In choosing the molding temperature for the molding step  108 , it will be understood that the melting point of the mixed blend may vary from case to case, depending on the relative wt % of the selected materials as well as the choice of the selected materials. In some examples, the molding temperature may range from around 65° C. to around 85° C. In the exemplary embodiment, the molding temperature used is 80° C. 
     The apparatus  200  further comprises a moveable mold component  218  that is configured to contact the stationary mold component  210  by relative movement of the moveable mold component  218  with respect to the stationary mold component  210  in a direction substantially parallel to direction arrow  220 . The moveable mold component  218  is provided with the mold cavity  214  into which the melt  600  is introduced through the sprue  212  in the stationary mold component  210  when the stationary mold component  210  and the moveable mold component  218  have been brought into contact with each other. The mold cavity  214  is provided with at least one interchangeable mold component  230 , and is preferably cylindrically shaped. 
     Referring also to  FIGS. 3A ,  3 B and  3 C, a preferred embodiment of the at least one interchangeable mold component  230  includes a first mold component  202  and a second mold component  300 . The first mold component  202  comprises an elongate hollow body and is configured to slideably engage the mold cavity  214 . The first mold component  202  comprises at least one through hole along a longitudinal axis  204  of the first mold component  202  such that the first mold component  202  is in the form of a hollow tube or sleeve and the at least one through hole is a central through hole  203 . The second mold component  300  is configured to form at least one elongate channel or hole in the molded part  500  along a longitudinal axis of the molded part  500 . The second mold component  300  is configured to slideably engage the longitudinal through hole  203  in the first mold component  202 , and is generally rod-shaped. 
     The first mold component  202  preferably includes an end surface  206  such as an end feature forming section or surface  206  configured to define an end surface of a product or part  500  formable in the mold cavity  214  in the molding step  108 . The feature forming surface  206  preferably comprises a surface having a plane perpendicular to the longitudinal axis  204  of the first mold component  202 . 
     In the molding step  108 , the second mold component  300  is extending from the first mold component to partially define a cavity for receiving the mixed blend forming the melt  600  to be molded to produce the molded part  500 . The second mold component  300  is preferably positioned adjacent the entry of the mold cavity  214  while the end feature forming surface  206  of the first mold component  202  is positioned at a distance from the entry of the mold cavity  214  such that a final mold cavity  214  defining a shape of the part  500  to be formed is defined by the internal surface  216  of the moveable mold component  218 , the end feature forming surface  206  and the second mold component  300  as shown in  FIG. 2A . During molding  108 , the melt  600  is injected into the final mold cavity  214  while both the first mold component  202  and the second mold component  300  are kept stationary as the melt  600  fills the final mold cavity  214  and is allowed to cool to form the part  500 . The stationary second mold component  300  thus defines an internal surface of the part  500  being formed while an internal surface  216  of the moveable mold component  218  defines a longitudinal external surface of the part  500 . Of the first mold component  202 , only the end feature forming surface  206  is in contact with the melt  600  to form the end surface of the part  500 . 
     At the end of the molding step  108 , the stationary mold component  210  and the moveable mold component  218  are moved apart and the molded part  500  is ejected. To eject the molded part  500 , the first mold component  202  is moved relative to the second mold component  300  in a direction shown by arrow  224  in  FIG. 3C , towards the entry of the mold cavity  214  parallel to the direction shown by arrow  220  in  FIG. 2A . In this way, the end feature forming surface  206  of the first mold component  202  pushes against the end surface of the molded part  500  to slide the formed part  500  off the second mold component  300  around which the molded part  500  has solidified. The second mold component  300  is thus arranged to be relatively retractable within and configured to cooperate with the elongate hollow body of the first mold component  202  for ejecting the molded part.  500  and for molding the molded part  500  respectively. 
       FIG. 4A  is an enlarged view of one embodiment of the interchangeable mold component  230  which is used in the molding apparatus  200  of  FIG. 2A . The interchangeable mold component  230  includes a first mold component  202  and a generally rod-shaped second mold component  300 . The first mold component  202  has an end feature forming surface  206 . The second mold component  300  has a surface configuration comprising a surface configuration of micro grooves  308  extending in a generally longitudinal direction on an outer surface of the second mold component  300 . The second mold component  300  extends longitudinally from the end feature forming surface  206  of the first mold component  202  during molding  108 . 
     As shown in  FIG. 4B , a part  500  producible by the interchangeable mold component  230  of  FIG. 4A  is a hollow tube  502  having an outer surface  504  defined by the inner wall  216  of the moveable mold component  218  and an inner surface  506  defined by the outer surface of the second mold component  300 . The inner surface  506  of the part  500  has a plurality of longitudinally extending micro grooves  508  formed thereon corresponding or complementary to the surface configuration  308  of the second mold component  300 . 
     After the molding step  108 , the method  100  further comprises processing the molded part  500  to remove one of the at least two biocompatible materials by a predetermined amount from the molded part  500  to produce the porous biodegradable medical implant device  700  having a physical shape and features as shown in  FIGS. 5A ,  5 B and  5 C. The device  700  includes micro grooves  708  corresponding to the microgrooves  508  of the molded part  500  formed by the microgrooves  308  on the second mold component  300  in the molding step  108 . Performing the processing step  110 ,  112  after the molding step  108  facilitates mass production of the device  700  with the desired overall dimensions and physical features including the micro grooves. In this manner, the difficulties of creating tubular structures by working with a porous material from the beginning may be circumvented. 
     The step of processing the molded part  500  includes a leaching step  110 . The leaching step  110  involves placing or immersing the molded part  500  in the predetermined solvent under appropriate conditions. The appropriate conditions include a predetermined period of time of immersion of the part  500  until a desired amount of one of the at least two biocompatible materials has been dissolved or leached off by the predetermined solvent. The leaching step  110  is stopped when the device  700  is observed to have a desired surface configuration, for example, having a surface structure as shown in the magnified image of  FIG. 5B . Alternatively, the leaching step  110  is stopped when the device  700  has reached a desired degree of porosity. In the exemplary embodiment where the selected biocompatible materials are PEG and PCL and the predetermined solvent is water, the leaching step  110  comprises immersing the molded part  500  comprising PEG and PCL in water for up to two days at a leaching temperature from 25° C. to 40° C. In other examples, the leaching step  110  may be carried out at a leaching temperature of 37° C., for 6 to 12 hours. The leaching temperature is selected to be lower than the threshold temperature. 
     Optionally, the processing step may further comprise a freeze-drying step  112  after the leaching step  110  to remove residual solvent from the device  700 . The freeze-drying step  112  involves subjecting the leached part  500  to carbon dioxide under supercritical conditions to further increase the degree of porosity in the device  700  produced. The freeze-drying step  112  may further be configured to stabilize the porous morphology of the device  700 . In some examples pores are formed on the wall of the device  700  from leaching of small molecular weight PEG and evaporation of water during freeze-drying of the molded part  500 . Thus, in the method  100  including the freeze-drying step, tubular structures are first molded before porosity is created by sublimation of ice during freeze drying as well as solubilization of trapped water-soluble polymer during immersing in water after the molding step  108 . 
     In the embodiment described above, the device  700  is in the form of a hollow tube with a porous wall having grooves on an internal wall as shown in  FIG. 5C . suitable for implantation into a living organism for guiding the growth of nerve cells and other tissues. 
     Traditionally, the fabrication of porous medical devices is performed in small batches or even by hand. This was previously particularly challenging as porosity tended to introduce irregularities and dimensional inaccuracy in small features. However, variations of the present method and apparatus enable the fabrication of such parts to enjoy the manufacturing efficiencies of high speed manufacturing processes such as injection molding. Additionally, dimensional accuracy, especially in the channels and lumens formed, can be achieved and maintained. 
     Advantageously, mechanical features such as channels or lumens that may help to prevent the medical devices from collapsing, kinking, or twisting undesirably may be easily formed. Furthermore, with the present method and apparatus with interchangeable parts, it is now easier to produce longitudinally oriented channels in a conduit (such as a medical device with one or more lumens) suitable for facilitating regeneration of nerve cells, or for producing functional conduits for use in kidney dialysis, etc. The channels and other longitudinal features may also increase the surface area available for cell contact. In addition, the low temperatures involved in the method and apparatus described above make it possible to incomorate drugs and other active materials into the medical device without additional post processing after the final parts have been obtained, and for the drugs or active materials to remain active. 
     To that end, the selecting step  102  of the method  100  may further include selecting at least one active material having a desired active property or nature, such as a medical, therapeutic, or like property, nature or effect. In some embodiments, the active material may be a drug or a bioactive agent. If the selected materials include at least one active material, the threshold temperature is selected to be lower than a temperature at which at least one of the active materials will be affected such that the active material will be rendered less effective in its respective medicinal, therapeutic or active property, nature or effect. Accordingly, where an active material is also selected in the selecting step  102 , the compounding step  104  will also include compounding the selected active material (such as a drug or bioactive agent) with the at least two selected biocompatible materials to form a polymeric mixed blend having the selected active material therein. 
     PCL has a slow degradation rate and better mechanical properties compared with other biopolymers such as polylactide. By introducing porous structures into a medical device comprising PCL, the degradation rate can be changed and even controlled by introducing different degrees of porosities to suit various applications. Porosity facilitates the delivery of drugs, such as growth factors, and of nutrition solution to desired sites. At the same time, desirable mechanical properties can be introduced to prevent conduit collapse. The described exemplary embodiment thus helps to increase the suitability of PCL for use in the fabrication of medical devices 
     It will be understood that various other combinations of materials and solvent may be selected in accordance with the criteria for selection taught above. 
     Optionally, the method  100  also includes a pelletizing step  106  after the compounding step  104  and before the molding step  108 . In the pelletizing step  106 , the polymeric blend (with or without at least one active material) is formed into pellets. This facilitates the provision of predetermined amounts of the compounded materials for the molding step  108 , including increasing the ease of feeding a predetermined amount of the compounded materials to a forming machine, such as the stationary mold component of the apparatus  200  as shown in  FIGS. 2A and 2B . 
     In an alternative molding configuration of the molding step  108 , for forming a high aspect ratio part  500 , the first mold component  202  and the second mold component  300  may be arranged in a configuration in the mold cavity  214  as shown in  FIG. 2B  before injection of the melt  600 . As can be seen in  FIG. 2B , the end feature forming surface  206  of the first mold component  202  is positioned adjacent an entry of the mold cavity  214  which is in turn adjacent the sprue  212  in the stationary mold component  210 . An end  306  of the second mold component  300  is also positioned adjacent the entry of the mold cavity  214 . In this alternative molding configuration, as the melt  600  is injected through the sprue  212  into the mold cavity  214 , the melt  600  comes into contact with the end feature forming surface  206  of the first mold component  202 . As the melt  600  continues to be injected through the sprue  212 , the first mold component  202  is moved back from the entry of the mold cavity  214  relative to the second mold component  300  in the direction shown by arrow  223 . The second mold component  300  is kept stationary. 
     Moving back the first mold component  202  during injection results in an increase in length of the mold cavity  214  around the stationary second mold component  300 , thereby allowing a corresponding increase in the volume of melt  600  around the stationary second mold component  300  as the melt  600  is being injected. Movement of the first mold component  202  is stopped when a desired length of the molded part  500  to be formed is reached, as shown in  FIG. 2A , where the second mold component  300  extends substantially beyond the end feature forming surface  206  of the first mold component  202 . 
     In the alternative molding configuration, the first mold component  202  is preferably actively moved back at a predetermined rate daring injection of the melt  600 . Active movement of the first mold component  202  during injection may optionally be configured to create a flow condition in the mold cavity  214  for facilitating inflow of the melt  600  into the mold cavity  214  smoothly to minimize air trapping. 
     Thus, by configuring the first mold component  202  to move during injection of the melt  600  in order to facilitate flow of the melt  600  into the mold cavity  214 , a high quality high aspect ratio part  500  may be formed having minimal air cavities therein. 
     Other shapes, sizes and configurations of molded parts are also envisaged, and may be realized by modifying the interchangeable mold component  230  accordingly. For example, another embodiment of an interchangeable mold component  400  is illustrated in  FIG. 6A . The interchangeable mold component  400  includes a generally cylindrical first mold component  401  having an end feature forming surface  402  and a second mold component  404  comprising a plurality of longitudinally extending rod-like elements  406 . The inner wall  216  of the moveable mold component  218 , the end feature forming surface  402  and the second mold component  404  together define a volume which determines the shape and size of a part  550  formed at the end of the molding step  108 . 
     The second mold component  404  extends longitudinally from the end feature forming surface  402  of the first mold component  401  during molding. The first mold component  401  comprises an equal number of longitudinal through holes configured to slideably engage the plurality of longitudinally extending rod-shaped elements  406  of the second mold component  404  for forming high aspect ratio molded parts  550  or for convenient ejection of the molded part  550  from around the second mold component  404  after molding. 
     As shown in  FIG. 6B , the part  550  may be a cylindrical shape  552  having an outer surface  554  defined by the inner wall  216  of the moveable mold component  218  an end surface  558  defined by the end feature forming surface  402  of the first mold component  401  and a plurality of internal longitudinal through channel or lumen  556  corresponding or complementary to the at least one element  406  of the second mold component  404 . 
     It will also be appreciated that other than micro groovoes  308  described above, the second mold component  300  may have other surface configurations, such as channels and larger grooves, or be smooth or have other predetermined surface finishes. 
     It is further envisaged that for the apparatus  200 , more than one mold cavity  214  may be provided in the moveable mold component  218 , and each mold cavity  214  may be provided with at least one interchangeable mold component  230  of any of the variations described above. 
     Whilst the foregoing description has described exemplary embodiments, it will be understood by those skilled in the technology concerned that many variations in details of design, construction and/or operation may be made without departing from the present invention. For example, the second mold component may comprise any practicable number of rod-shaped elements as may be desired to form a corresponding number of longitudinal through holes in the molded part. The stationary mold component may be moved away from the moveable mold component before and after molding while keeping the moveable mold component stationary. The mold cavity may have a different cross-section other than a uniform circular cross-section to form the cylindrical shape. For example, the mold cavity may have an elliptical cross-section. The cross-section of the mold cavity may also vary in size and shape along the length of the mold cavity according to the shape of the molded part that it is desired to form.