Patent Application
20200253740
The present invention relates to orthopedic implants and surgical tools for small joints in human, imaging technologies, image processing techniques and additive manufacturing techniques applied to the fabrication of medically relevant articles.
A small joint bone implant's fitness to individual patient's anatomy is strongly correlative to the efficacy of treatment of pathologies—including trauma, tumors, rheumatoid and osteoporosis—that call for bone replacement. Misfit between the shapes and dimensions of implant and those of the patient's natural bone(s) has been constantly found a major cause of limited functionality of the implanted organ, and post-treatment injuries due to, among other things, bone fatigue or wearing of intramedullary cavity into which the implant has been inserted. Even for an internationally accepted standard, a small joint bone implant is expected to maintain only a passable performance—that is, until the pain or reduced mobility necessitates a follow-up operation.
This fitting problem is not limited to the matter of size and shape: individual's each bone, including cortical and cavity parts, has distinctive angles, curvatures, dents, protrusion, and other non-uniformities, which may vary further owing to the natural configuration of neighboring bone(s) or deformation caused by the pathology. Such complexity has long aggravated the inadequacy of pre-manufactured, standardized implants (however many sizes available they are) as well as the difficulty of fabricating an implant that truly satisfies each patient's anatomical needs.
In respect of the bone operation process, surgeons in the relevant technical fields recognize the need to preserve as much of patient's natural bone as it is practical, which often conflicts with the need to remove all defective parts. Said decision-making is further constrained by the other needs to operate the patient with minimal consumption of time and damages to adjacent muscles and tissues. Usage of conventional surgical tools, e.g. a cutting guide, suffers a similar vexation: a pre-manufactured tool offers a poor fit with the patient's anatomy, resulting in a suboptimal operation speed, precision, and stability. In many cases, especially where the angle of bone resection is an important factor, a cutting error may compel the surgeon to relocate the position to be sawn off.
Prosthesis that is not sufficiently patient-specific also causes problem while it is being implanted: often the surgeon is forced to change the implant selection/combination, or manually reconfigure the implant mid-operation; worse, some would opt to scrape the intramedullary cavity—thinning the bone even further—to fit a natural bone to an inflexible implant.
Apart from being illustrative of a treatment system that is sluggish and painful, the above factors also add to the patient's slow recovery and risks of developing post-operation injuries.
Use of standardized prostheses also entails logistical costs, including inventory management and transportation. To enable the patient's access to the treatment, parties along the supply chain, in many cases the government, has to bear such costs.
U.S. Pat. No. 8,353,965 to Seitz Jr. William H and Santilli Albert N discloses a custom set of small joint orthopedic implant, a surgical tool (i.e. a rasp for cleaning the intramedullary cavity before insertion of implant), and an impact tool, all of which having corresponding dimensions. These modules are preferably fabricated by machining means. Their dimensions are approximated from the scaled 2-dimensional radiography of the patient's relevant bones. This method accurately captures only the bone head's height and width, while letting finer features (e.g. dents and curvatures) elude, affecting significantly the anatomic fitness of resulting implant. The stem of this implant is preferably projecting straight along a longitudinal axis. This arrangement disregards the curved, non-uniform outline of intramedullary cavity which is particularly conspicuous where the cavity is further from the joint, meaning the implant per this patent is good only where the receiving bone cavity is straight, for example, a position past radial tuberosity. Moreover, the dimensions of this implant are determined from a set of dimension matrices, according to which the difference between each order of size is often millimeters. The implant resulted from this approach is at best an estimate, subject to mid-operation adjustments to attain fitness for insertion.
U.S. Pat. No. 7,452,381 to Mayo Foundation for Medical Education and Research discloses a radial head replacement system (also referred to as a toolkit) which takes into account a flexible spatial relationship between the bones and prostheses. In this case, a set of screws is used to affix the head with the stem at any desired angle, and a cutting guide is capable of being slid along the axis of defective bone and adjusted for angled osteotomy. Still, the said workings have to be carried out manually mid-operation, and this system requires twice resection of the bone. This does not improve much of the speed and accuracy.
The abovementioned have demonstrated that the current state of the art is conceptually fragmented and offers neither a small joint implant nor an implanting system that is actually (or even sufficiently) patient-specific.
The present invention pertains to a single orthopedic implanting system that addresses all the aforementioned problems. Said system is integrated both vertically (i.e. from the manufacture of implant to completion of surgery) and horizontally (i.e. relevant to a wide range of raw materials, positions of the defective small joint, and natures of pathology). Enablement of the present invention is based upon the inventive concept of wholly patient-specific design of implant and surgical tools obtainable from the same means of manufacture.
An existing technique capable of generating a 3-dimensional image of human interior, including but not limited to CT-scan and MRI, is utilized to capture true-to-scale 3-dimensional images of relevant bone(s). This is to find reference points for the position of osteotomy, surgical tool placement, and shape of implant. Since a human's bone counterparts (e.g. left-arm's and right-arm's elbow joint) are not identical, the optimal reference points are obtainable from the images of the small joint bone subject to resection (e.g. the pathological bone). If said bone is so damaged that effective reference points cannot be located, the reference points may instead be found on the processed mirrored image of that bone's counterpart (i.e. the one not subject to resection). Because the detailed topography of the bone (dents, bumps, curvatures, etc.) is captured by this technique, the reference points are not required to be as protrusive as a tuberosity to produce the effective patient-specific fitness; an aggregate of those bits of “biometric” marks would be sufficient. It is also contemplated that images from both counterparts are used for said purposes. Determination as to whether a bone has been so damaged that the required reference points are unobtainable from an image thereof can be made by an ordinary orthopedist skilled in the relevant art.
The ability to utilize inconspicuous natural bone marks as reference points makes the system in accordance to the present invention applicable to small joints in any bodily positions and for a broad range of pathologies. For instance, riddance of the need to refer the positioning of cutting guide to a radial tuberosity enables a patient-specific treatment even where the radial tuberosity has decayed because of bone cancer.
Fabrication of the implant and other apparatuses in the system in accordance with the concept of this invention relies upon the abovementioned images, any existing additive manufacturing machine (i.e. a 3-D printer) and any orthopedically accepted 3-D printing materials, including titanium alloys and stainless steels. Resulting objects will be truly patient-specific, that is, providing the effective fitness to one patient alone and not to any other, and more effective fitness to that one patient than the implant and surgical tool fabricated otherwise. This better fit offers optimal functionality (e.g. mobility of the implanted joint) and minimal post-operation bone fatigue or pain.
In one embodiment, a 3-D printed implant includes a head and a stem. Manufactured by this means, the head will feature a complex shape that fits tightly to its adjacent bone(s). In another embodiment, the stem could be made as short or long, straight or curved, smooth or uneven, as the receiving bone cavity's anatomy and pathology may require. In yet another embodiment, the spatial relationship, i.e. angle, between the head and the stem may be reproduced with fidelity to the patient's natural bone. According to another embodiment of the present invention, the stem may be grooved along its axis, or the stem's surface may be designed otherwise to aid the flow or adhesion of bone cement, which in turn facilitates the bone ingrowth.
In one embodiment, a surgical tool fabricated in accordance with the present invention can effectively interlock the cortical bone area over which it is placed. This maximizes friction between the tool and the bone to be operated upon while minimizing the contacting surface area required for supporting the guide affixation, and thus prevents more surrounding muscles and tissues from being excessively damaged and enables more speed and accuracy of the operation. This concept is applicable to a range of surgical tools, including a cutting guide, screwing guide and bone plate.
A preferable example of implanting surgery performed in accordance with the present invention involves performing the extensor digitorum communis tendon (EDC) splitting approach to open EDC and radial collateral and annular ligaments around the site of the operation. The surgeon may choose any other conventional technique that is suitable for each patient's particular case. Said operation, when performed using the implant and surgical tool fabricated in accordance with the present invention, requires minimal involvement of healthy tissues, muscles, and bones; minimal “cleaning” of the receiving bone canal; a few pieces of apparatuses; one time of bone resection and implant insertion; and no mid-operation trial-and-error or manual adjustment. In combination with the improved speed and accuracy, the patient would enjoy a quicker recovery.
The present invention also allows an operation by which (a) pre-pathologic imaging and collection of images of relevant joints is carried out in anticipation of future surgery; and/or (b) the logistical problem is overcome by separating the premises where the images are taken from where the images are stored or processed from where the implant and surgical tool is actually fabricated, and wherein the unprocessed or processed images are transferrable between these premises by known means of telecommunication or computer network.
Reference will now be made in detail to the various embodiments of the present invention illustrated in the accompanying drawings. Wherever possible, the same or like reference numbers will be used throughout the drawings to refer to the same or like features. It should be noted that the drawings are in a simplified form and are not drawn to precise scale.
Furthermore, the described features, advantages, and characteristics of the exemplary embodiments of the present invention may be combined in any suitable manner in one or more embodiments. One skilled in the relevant art will recognize, in light of the description herein, that the present invention can be practiced with one or more of the specific features or advantages of a particular exemplary embodiment. In other instances, additional features an advantages may be recognized in certain embodiments that may not be present in all exemplary embodiments of the present invention.
THE IMPLANT.
In one embodiment, A head 110 may have dimensions, shape, and topography corresponding to the anatomy of a small joint bone's head. Said anatomy may be based on a three-dimensional image of a small joint bone subject to resection, or a processed mirrored three-dimensional image of the bone not subject to resection. Owing to the fact that the configurations of two pieces of bone cannot be identical, even though they are limb counterparts of the same person, the best result is obtainable from an image of the small joint bone subject to resection, but the choice of referenced image will ultimately be decided by the responsible doctor. For example, if the small joint bone subject to resection is excessively deformed, the doctor may choose to reference the head to the processed mirrored image of the bone not subject to resection instead, which still gives a sufficient and effective patient-specific fit with the patient's anatomy.
In one embodiment, a stem 120 has dimensions and shape corresponding to the anatomy of the intramedullary cavity of the bone into which the stem is intended to be inserted. In an embodiment. A stem 120 is made straight, protruding from the head 110 along a longitudinal axis, as shown in
As shown in
In addition to the above embodiments, other surface or structural architectures may be applied to the implant pursuant to the means of fabrication to be described below. Example embodiments, which may be present separately or integrally, are shown in
Further, in embodiments disclosed in
In any example embodiment from
The inventors have contemplated that the concept of the present invention (i.e. the fabrication of a stem and that a stem may be detached or fabricated separately from a head) may be applied to fabricate another embodiment, which is an orthopedically compatible object for insertion into an intramedullary cavity of a small joint bone's shaft having patient-specific dimensions and shape which correspond to anatomy of said intramedullary cavity, though serving a different function from the stem. Said orthopedically compatible object may include a spacer, which is used for a temporary insertion into the bone cavity.
The concept in accordance with the present invention may as well be flexibly applied to fabricate implants or orthopedically compatible objects suitable for different small joint bones. In an exemplary embodiment shown in
THE SURGICAL TOOL.
In an embodiment shown in
In one embodiment, where the resection site 220 is close to a conspicuous bone protuberance, such as a tuberosity (212 or 213), the cutting guide 300 is tailored to feature a hollow 340 of a size sufficient to accommodate the base of the conspicuous bone protuberance, so that the latter is used as another reference point for an improved interlocking the cutting guide 300 against the bone shaft 210.
The edge 320 of the cutting guide 300 may be configured so that it has a predetermined angle (not shown) to the axis of the bone shaft 210 to accommodate an angled resection. This variation depends on each patient's specific needs, which may arise from the nature of patient's own anatomy, or their pathology.
In another embodiment as shown in
In another embodiment as shown in
In another exemplary embodiment shown in
In yet another embodiment as shown in
The concept in accordance with the present invention may as well be flexibly applied to fabricate surgical tools suitable for different small joint bones. In an exemplary embodiment shown in
IMAGING, SELECTION AND PROCESSING OF THE BONE IMAGE AND DEVELOPMENT OF THE SAME FOR THE FABRICATION MODEL. The process begins with obtaining the three-dimensional image of relevant bone(s). Existing apparatuses that are capable of said imaging include CT-scan and MRI, which are well-understood among the persons skilled in the art.
The most preferable (and in most cases necessary) three-dimensional image is one obtained from the same bone that hosts the resection site. The image of the bone subject to resection will then be diagnosed by accepted medical means to pinpoint the resection site 305, along with the angle of resection, and then to determine on a case-by-case basis whether the same image is good for being used as a fabrication model. If not, then a three-dimensional image of a bone not subject to resection on the opposite side of patient's body is of the second preference.
In the case where the image of the bone not subject to resection is selected, said image is mirrored by techniques known to a person skilled in the art. Preferably, the mirrored image is then processed through a process comprising the steps of registration, morphological measurement, head reconstruction, cartilage compensation, stem design and surgical tool design. These steps may be implemented in more than one possible sequence, and thus the sequence to be disclosed in the following paragraphs are not necessarily chronological. The objective of these steps is to develop the fabrication model which is the closest approximate of the bone subject to resection, using the mirrored image of the bone not subject to resection as a starting basis. Preferably, the reference location for registering the contralateral side (mirrored image) with the bone subject to resection is determined by the area of prominent topography of the bone. In an exemplary embodiment, the area of radial tuberosity combined with 2 cm of proximal diaphysis is selected as a registration reference for designing a radial head prosthesis.
The bone images used in the registration process may be exclusive of their small joint parts, but more preferably inclusive of their small joint parts. In some cases, the injury or deformation occurred to the small joint part of the bone subject to resection may be so severe that it is infeasible to include the images of small joint part into the basis of registration. In such a case, the registration may be carried out based on the bone images exclusive of their respective small joint parts without deviating significantly from the technical effects in accordance with the concept of present invention.
Registration in accordance with this present invention may be based upon either intensity or feature, or both. In the intensity-based registrations, the bone images are aligned with reference to their intensity patterns obtainable from the scanner, e.g. CT-scan and MRI; in the feature-based registrations, the bone images are aligned with reference to their topographic features, e.g. dents, bumps, curvatures, etc. This registration process is preferably carried out automatically with an aid of at least one computer device.
The result of registration process is a transformation matrix whereby the positional data of each 3-D bone image (also known as point cloud data) is transformed into a plurality of transformation matrices having 4×4 dimension. Mathematically, if one data set (e.g. fractured bone) is transformed using the obtained transformation matrix, it will be translated and rotated in such way that it will be finally aligned with the other reference data (e.g. mirror of the healthy bone).
Aligning in accordance with the present invention means aligning the relevant part of the mirrored image of the bone not subject to resection with the relevant part of the bone subject to resection through the transformation matrices. Particularly, said aligning is performed upon a rigid-body basis—that is, only by ways of rotation and geometric translation, but not scaling. Even more particularly, the objective of said alignment is to transform, map, or overlay the two 3-D images in the manner that the volume of common space occupied by both images is maximized, and the volume of space occupied by only either of the two images is minimized. Said objective may be effectively realized by the use of one of several mathematical algorithms known to a person skilled in the art, preferably one which enables interpolation of the values assigned to each voxel selectable from any of known image re-sampling methods, including nearest neighbor, linear interpolation, cubic convolution, and Lanczos algorithm. More preferably, said mathematical method is Lanczos algorithm or a modified algorithm based on Lanczos algorithm.
Morphological measurement in accordance with this present invention means “measuring” the anatomical geometry of the to-be-fabricated implant of small joint bone head and/or stem based on point cloud data. In a preferable embodiment, said point cloud data are those which have been processed in accordance with the foregoing registration step. Said point cloud data are then subject to a combination of image processing techniques, including and selectable from the search of points and nearest neighbors method, nonlinear least-square method for line and planar fitting, ellipse-fitting method, iterative surface fitting method, principal component analysis and orthogonal projection, or modified methods based on said methods. These techniques are preferably carried out automatically with an aid of at least one computer device. The details of separate enablement for each of said methods are known to a person skilled in the art.
The data obtainable from the morphological measurement includes the parameters defining the size and geometrical characteristics, and variation thereof, of the patient's bone, which will be used for the fabrication of the implant. In an embodiment, the parameters for the small joint bone head obtainable from the morphological measurement are ones defining the head's anatomical contours, including the head diameter, dish diameters, articular depth, dish offsets, and end plate angles. In another embodiment, the parameters for the small joint bone intramedullary cavity obtainable from the morphological measurement are ones defining the cavity's anatomical clearance, including canal orientation, maximum diameter, minimum diameter and canal length.
Head reconstruction in accordance with this present invention means a step for additional correction of the bone head image with reference to the available anatomical geometry. The reconstruction may follow the “native” or “anatomical” strategy, depending on the condition of the head of the bone subject to resection. In an exemplary embodiment, where the images of fractured bone head pieces may by reassembled digitally, the “native” reconstruction is adopted, whereby the reassembled image is the basis for an additional correction of mirrored bone head image. In another exemplary embodiment, the “anatomical” strategy is adopted, whereby the parameters obtainable from the morphological measurement are the basis of additional correction. In both foregoing exemplary embodiments, the corrected (i.e. reconstructed) bone head image will be further developed towards the final 3-D digital fabrication model.
Cartilage compensation in accordance with this present invention means a step for additional correction of the bone head image with reference to the thickness of articular cartilage, the dimension of which may not be fully captured by the currently available imaging devices (e.g. a CT scanner) and thus failure to take this thickness into consideration may result in a fabrication of prosthesis bone head which is about 0.5-2.0 mm smaller than the dimension that is effectively patient-specific. In one embodiment, the cartilage compensation is carried out in a uniform fashion whereby the same additional thickness is applied to both the bone head image's fovea and rim. In another embodiment, the cartilage compensation is carried out in a non-uniform fashion whereby the variation of thickness values is applied at different locations of the bone head image. In all the foregoing embodiments, the corrected (i.e. compensated) bone head image will be further developed towards the final 3-D digital fabrication model.
The stem design in accordance with this present invention means a step for development of the stem part of the fabrication model of bone implant, based on, among others, the dimensions, the measured intramedullary cavity's morphological parameters, and other features which may facilitate the insertion or fitting of the implant stem with the intramedullary cavity, or features that may be preferable or required for each patient's conditions. In an exemplary embodiment, the stem is straight. In another exemplary embodiment, the stem axis follows a customized, patient-specific curve to fit with the patient's anatomical requirements. In yet another exemplary embodiment, the stem surface is configured to have a surface property that prevents rotation or aids the distribution or flow of bone cement, e.g. by a fluted design. In a further exemplary embodiment, the stem has a porous structure or rough surface to promote the bone ingrowth activity. In an even further exemplary embodiment, one or more small holes is created in order to be used for temporary fixation by a wire or screw or a plurality or combination thereof.
The principle similar to the abovementioned stem design may be applied to develop a fabrication model for an orthopedically compatible object, which, despite being intended for insertion into an intramedullary cavity of a small joint bone's shaft, is not intended to be inserted in connection with a prosthesis bone head, and so benefits from the patient-specific morphological parameters of an intramedullary cavity in a similar manner to a prosthetic stem while not being classified as a stem. Examples of said orthopedically compatible objects intended for insertion into an intramedullary cavity of a small joint bone's shaft include a spacer.
The head bone image that has been subject to all necessary registrations and corrections will be combined with the stem image designed in accordance with the foregoing paragraph to form the entire fabrication model for a patient-specific small joint implant.
The surgical tool design in accordance with this present invention means a step for development of the fabrication model for a surgical tool as preferred or required for the resection to be performed. The design will be based on (i) the inverse patient-specific anatomical topography of the small joint bone surface which is obtainable from the aforementioned imaging apparatus and which the surgical tool is intended to interlock during the surgery and (ii) other functional aspects of the surgical tool which are known by the person skilled in the art (see below examples). The inversion of anatomical topography of the small joint bone surface may be performed by any means for image processing known to the person skilled in the art.
FABRICATION OF THE IMPLANT AND SURGICAL TOOL. After the image of fabrication model has been determined and digitized, a head (e.g. 110, 111, 113, 116, 170) and/or a stem (e.g. 120, 121, 123, 124, 125) and/or an angle 130 and/or the surgical tool (e.g. 300, 360, 400, 500, 560) is fabricated using a 3-D printer, otherwise known as an additive manufacturing machine. The material used in fabrication could be any one recognized as appropriate for the task by a person skilled in the art. Examples of workable materials include those in the family of titanium alloy, cobalt chrome, stainless steel, zirconium alloy, tantalum alloy, polymers or cements. Control and configuration of the 3-D printer depends on the materials used and customization of the part fabricated, which is well within the existing 3-D printing technology.
The dimensions, shape, and topography of a head (e.g. 110, 111, 113, 116, 170) and a surgical tool (e.g. 300, 360, 400, 500, 560) will conform to their respective image used as reference, taking into account the location and angle at a resection site (e.g. 220, 221). It is to be noted that, for the case of a surgical tool, the topography of the bone is inverse to enable an inner surface (e.g. 310, 311) that fits over the cortical surface of bone shaft (e.g. 210, 211, 214, 216).
On the other hand, fabrication of a stem (e.g. 120, 121, 123, 124, 125) and an angle 130 between the head and the stem only needs to refer to the dimensions and shape of the selected image and the location and angle at the resection site—the topography is not relevant here.
In certain embodiments, the stem 120 could be fabricated to be straight as shown in
It is preferable to fabricate all the above implant (e.g. 100, 101, 103, 104, 105) and surgical tool (e.g. 300, 360, 400, 500, 560) to constitute a wholly patient-specific small joint bone implanting toolkit. However, the fabrication of only part of the toolkit is also possible, as an incomplete toolkit would still offer technical advantage in respect of the part that is made patient-specific.
The fabrication process could be broken down into parts, each of which may be carried out in different physical locations and by different entities. This provides flexibility of logistics and fund management. For example, a doctor who runs a personally-owned clinic may choose to collect the images of relevant bone themselves, and then send the images to a third-party 3-D printing service who will fabricate the patient-specific implanting toolkit or part thereof, which will later be delivered to the doctor. This way the doctor is spared of the need to own or maintain a 3-D printer in their own clinic.
Possibly, anyone may choose to take and store images of the relevant bones when they are of fine health, in anticipation of a future possibility where a bone surgery is needed. Alternatively, the present invention may be used to fabricate the toolkit by interpolating the information from an aggregate of digitized bone images obtained from a very large sample size, e.g. national database.
THE INSTALLATION OF IMPLANT. The implanting process begins with determining the resection site (e.g. 220, 221) and angle (not shown) of bone resection to be performed upon a bone shaft (e.g. 210, 211, 214, 216). This step requires a three-dimensional image of bone subject to resection and is carried out in parallel with the fabrication of implant and surgical tool, as explained above.
Next, the surgery technique that is understood by skilled bone surgeon is performed to open the skin, flesh, muscle, tendon, etc., to provide the optimal clearance around the site of operation and expose the small joint bone, which is then cleaned as preparation for the resection. The surgeon may choose any conventional technique that is suitable for each patient's particular case.
After the implant and surgical tool are ready, the cutting guide (e.g. 300, 360, 400) is temporarily fitted over a cortical surface of a bone shaft (e.g. 210, 211, 214, 216) to mark resection site (e.g. 220, 221) with its edge (e.g. 320, 322). The inner surface (e.g. 310, 311), having configured to conform to the inverse topography of the bone, and in some cases featuring a hollow (e.g. 340), will interlock all the reference points (i.e. irregularities including small dents, bumps or even conspicuous protuberance, such as tuberosity 212, 213 or 217), providing a sufficient friction that prevents the cutting guide from sliding laterally over the cortical surface of the bone shaft during the resection, as long as a certain amount of pressure is applied, manually or by an external tool's aid, pushing the cutting guide against the bone shaft. Resection is performed at the resection site which is located by the edge, using a saw which could be manual or driven by an external power source, at an angle predetermined by the edge. The resection will be completed when the bone head (e.g. 200) has been separated from the bone shaft (e.g. 210).
Subsequently, the intramedullary cavity (e.g. 211, 219) and internal wall (e.g. 218) is cleaned by implementing a broaching guide 560. Then the implant (e.g. 100, 101, 103, 104, 105) is inserted into the intramedullary cavity of the resected bone shaft (e.g. 210, 211, 214, 216). The bottom part of the implant head (e.g. 110, 111, 113, 116, 170) will sit directly upon the resected rim (e.g. 222, 223, 224). In some cases bone cement is used to aid the adhesion, which is not shown on the Figures.
The wound from the surgery is then sealed by means known to a skilled person, and the patient is sent for further recuperation.
Although the Figures referred above concerns implants, fabrication, and implantation of an elbow's radial head bone, such was meant for exemplifying purposes only. The principle of the present invention equally applies to any small joint of a human body, including neck, spinal cord, shoulder, elbow, wrist, hand, fingers, hip, knee, ankle, foot, toes. Applications in relation to said small joints are readily appreciated by a person skilled in the art in light of the above descriptions concerning the radial head alone.
While the present invention has been described with reference to exemplary embodiments, it will be appreciated by those skilled in the art that various changes may be made and equivalence may be substituted for elements thereof without departing from the scope of the present invention. It is to be understood that the present invention is not limited to the particular aspects of the exemplary embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as disclosed above.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/TH2018/000035 | 8/8/2018 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62542914 | Aug 2017 | US |
