Patent Application
20220370185
Except for human donor transplant, attempts at replacing organs or parts of an organ, can be classified into two main approaches, which although sharing some common aspects, are fundamentally different. One is related to Regenerative Medicine and Tissue Engineering and the other is the Artificial or Prosthetic approach. The former relies on cell lineage evolution, self-assembly and reorganization of live primordial cell lines with or without the use of differentiator promoter molecules with the goal to regenerate functional tissue structures (1,2)
The second, provides largely artificial substitutes, functionally ready to ameliorate or replace the role of an organ (3).
The aim of this invention is to provide mechanisms for designing prosthetic organ tissue as a scaffold for regenerative organization of organ tissue for organ function supplementation or replacement.
For purposes of clarity, the following terms used in this patent application will have the following meanings:
The terminology used herein is for the purpose of describing example embodiments only and is not intended to be limiting. As used herein, the singular forms “a,” “an,” and “the” may be intended to include the plural forms as well, unless the context dearly indicates otherwise. The terms “comprises,” “comprising,” “including,” and “having,” are inclusive and therefore specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the order discussed or illustrated, unless specifically identified, as an order of performance, It is also to be understood that additional or alternative steps may be employed.
When an element or layer is referred to as being “on,” “engaged,” “connected,” or “coupled” to or with another element, it may be directly on, engaged, connected or coupled to the other element or layer, or intervening elements or layers may be present. In contrast, when an element is referred to as being “directly on,” “directly engaged to,” “directly connected to,” or “directly coupled to” or with another element or layer, there may be no intervening elements or layers present. Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g., “between” versus “directly between,” “adjacent” versus “directly adjacent,” etc.). As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
Although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms may be only used to distinguish one element, component, region, layer or section from another region, layer or section. Terms such as “first,” “second,” and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the example embodiments.
Spatially relative terms, such as “inner,” “outer,” “beneath,” “below,” “lower,” “above,” “upper,” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. Spatially relative terms may be intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as “below”, or “beneath” other elements or features would then be oriented “above” the other elements or features. Thus, the example term “below” can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.
“Substantially” is intended to mean a quantity, property, or value that is present to a great or significant extent and less than, more than or equal to total. For example, “substantially vertical” may be less than, greater than, or equal to completely vertical.
“About” is intended to mean a quantity, property, or value that is present at ±10%. Throughout this disclosure, the numerical values represent approximate measures or limits to ranges to encompass minor deviations from the given values and embodiments having about the value mentioned as well as those having exactly the value mentioned. Other than in the working examples provided at the end of the detailed description, all numerical values of parameters (e.g., of quantities or conditions) in this specification, including the appended claims, are to be understood as being modified in all instances by the term “about” whether or not “about” actually appears before the numerical value. “About” indicates that the stated numerical value allows some slight imprecision (with some approach to exactness in the value; approximately or reasonably close to the value; nearly). If the imprecision provided by “about” is not otherwise understood in the art with this ordinary meaning, then “about” as used herein indicates at least variations that may arise from ordinary methods of measuring and using such parameters. In addition, disclosure of ranges includes disclosure of all values and further divided ranges within the entire range, including endpoints given for the ranges.
Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the recited range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
References to “embodiment” or “variant”, e.g., “one embodiment,” “an embodiment,” “example embodiment,” “various embodiments,” etc., may indicate that the embodiment(s) or variant(s) of the invention so described may include a particular feature, structure, or characteristic, but not every embodiment necessarily includes the particular feature, structure, or characteristic. Further, repeated use of the phrase “in one embodiment,” or “in an exemplary embodiment,” do not necessarily refer to the same embodiment or variant, although they may.
As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.
The term “material” is intended to refer to elemental metals, alloyed metals or pseudometals.
For purposes of this application, the terms “pseudometal” and “pseudometallic” are intended to mean materials which exhibit material characteristics substantially the same as metals, Examples of pseudometallic materials include, without limitation, composite materials, polymers, and ceramics. Composite materials are composed of a matrix material reinforced with any of a variety of fibers made from ceramics, metals, carbon, or polymers.
As used in this application the term “layer” is intended to mean a substantially uniform material limited by interfaces between it and adjacent other layers, substrate, or environment. The interface region between adjacent layers is an inhomogeneous region in which extensive thermodynamic parameters may change. Different layers are not necessarily characterized by different values of the extensive thermodynamic parameters but at the interface, there is a local change at least in some parameters. For example, the interface between two steel layers that are identical in composition and microstructure may be characterized by a high local concentration of grain boundaries due to an interruption of the film growth process. Thus, the interface between layers is not necessarily different in chemical composition if it is different in structure.
The term “build axis” or “build direction” is intended to refer to the deposition axis in the material. For example, as a material is being deposited onto a substrate, the thickness or Z-axis of the material being deposited will increase, this is the build axis of the material.
The terms “circumferential” or “circumferential axis” is intended to refer to the radial direction of a tubular, cylindrical or annular material or to the Y-axis of a polygonal material.
The terms “longitudinal,” “longitudinal axis,” or “tube axis” are intended to refer to an elongate aspect or axis of a material or to the X-axis of the material.
The term “bulk material” is intended to refer to the entirety of the material between its surfaces.
The term “film” is intended to encompass both thick and thin films and includes material layers, coatings and/or discrete materials regardless of the geometric configuration of the material.
The term “thick film” is intended to mean a film or a layer of a film having a thickness greater than 10 micrometers.
The term “thin film” is intended to mean a film or a layer of a film having a thickness less than or equal to 10 micrometers.
The terms “physical vapor deposition” and/or is acronym “PVD” is intended to encompass sputtering, electron-beam deposition, hot-boat evaporation, reactive evaporation, ion platting, plasma sputtering and/or ion beam sputtering.
It may be argued that artificial replacements have had a broader impact in medicine, in part due to their longer history of development and because they have readily benefited from the latest technological advances in materials science, fabrication and microelectronics. Implantable devices are currently common tools of practice in several medical specialties: Ocular lens implants have been time-proven in ocular surgery (4) and cochlear implants are becoming increasingly sophisticated (5). Cardiac pacemakers and ICD (implantable cardioverter defibrillator), are probably the most successful standalone microelectronic implants so far (6). In orthopedic surgery, rehabilitation of knee function due to osteochondral degenerative changes currently uses both approaches: intra capsular introduction of cartilage building promoters (7) and total artificial joint replacement (8). Given the importance of life-style changes in patients with knee joint disease and the need to quickly restore them to deambulation, the prosthetic approach has been the most widely adopted. Other prosthetic joint substitutes like the artificial hip joint, have reached state-of-the art status, with high safety and efficacy (9). Osteo-integrated dental implants have significantly advanced prosthetic dentistry (10
Implantable cardiovascular prosthetics have been very effective and enjoy a long history of successful development: Surgical and transluminal vascular grafts and stent grafts and prosthetic cardiac valves (11), caval filters (12) coronary stents (13,14), patent foramen ovale occluders (15), atrial appendage closure devices (16) mitral valve repair clip (17), transluminal aortic valve replacement (18) among many others, already available or in development.
Regenerative strategies have been attempted in the cardiovascular system, but they have not been quite as successful as prosthetic devices. Cardiac muscle regeneration was attempted with intracoronary infusion of myoblasts (19). Also, cardiac muscle injection of progenitor cells was evaluated in patients as a therapy for no-option angina (20). The improvements achieved with these approaches have been modest at best and inconclusive insofar the claimed mechanism of action (21). Myocardial revascularization with gene therapy promoting angiogenesis (22) or implantation of endothelial progenitor cells (EPG's) has yielded modest or controversial results (23).
Bioresorbable vascular stents (BRS) can be considered a regenerative approach insofar as the theory upon which they are based. Founded on the assumption that the diseased vascular wall tissues would reorganize into functional structures, vasomotion and positive remodeling was expected concurrently with the disappearance of the scaffold (24). Although the BRS proved equivalent to drug eluting metal stents in pivotal randomization trials (25) they have been clinically abandoned as post-approval clinical evidence cast doubts about their safety and efficacy (26). Some late thrombotic events with the BRS coincided in time with complete scaffold reabsorption supporting the notion that a permanent stent scaffold may be needed to replace the loss of the arterial connective structure. This is an important component of atherosclerotic vascular occlusive disease as the vessel structure supports endothelial cell function and stability (27).
Progenitor stem cells (PSC) from fetal tissues, umbilical cord, bone marrow, or fibroblast cell lines (28) can be induced to produce mature lineage cells as neural, hepatic, cardiac, renal and so forth (29). This brought about a large and ongoing body of research based on the possibility of regeneration of organs for in vitro or in vivo applications (30).
At present, the creation of fully functional isolated organs from progenitor cells appears rather remote from current perspective (31,32), but substantial work is being done with infusion of progenitor cells in diseased organs aiming at replacing cellular loss. While there are currently more than twelve hundred mesenchymal stem cell (MSC) clinical trials (Clinical trials.gov) large scale, controlled clinical studies have often failed to substantiate the benefit suggested by smaller trials (33).
The co-location of constituent cells in the correct position and arrangement in an artificial or biological matrix has been attempted by recellularization of decellularized organs like lungs (34) and cardiac valves (35). Work with 3D printing of cells and viscoelastic matrices is progressing through preliminary stages (36). The use of porous hydrogels or bioresorbable materials such as polyglycolic acid as tissue scaffolds rely on the expectation that progenitor cells will home, assemble, differentiate and promote the formation of their own support infrastructure including vascular supply and lymphatic/venous drainage among other tissue architectural features. Based on currently available experimental evidence, it seems that the expectation of spontaneous generation of tissue infrastructure may be over optimistic. Engineered prosthetic cellular scaffolds may be more realistic tissue platforms as conceptualized by constructs such as suggested in
It will be understood that alternative architectures of PECM arrangements are both intended and contemplated by the present invention other than the specific example illustrated in
Prosthetic scaffolds may be more plausible as engineered extracellular matrices may guide cell growth, location and differentiation to achieve the goal of functional semisynthetic organs. As these fledging efforts progress through basic science proof of concept to eventual practical reality, it is not inconceivable that future replacement organs will be bioprosthetic constructs rather than all-biological laboratory organs ready to be surgically implanted like donor allografts. Practically speaking, prosthetic constructs have logistical advantages compared to biological constructs insofar control of measurable parameters, fabrication techniques and reproducibility. Controlled progression to increasing complexity is another advantage of prosthetics and may translate into more predictable and consistent results.
Organ transplantation of live or decellularized tissue may not be considered regenerative therapy since the transplanted organ or parts of an organ, whether it be a homograft, allograft or xenograft is functionally developed and aims at readily substitute a diminished or absent function. Optimally, live donor transplant is well tolerated by the recipient provided MEW, HLA, ABO compatibility, adjuvant chemotherapy and prevention of infection and other potentially adverse events (37). Although not a solid organ, allogenic or autologous transplants of blood precursors in the bone marrow routinely restore blood cell production in patients with bone marrow depletion by chemo or radiation therapy. However, blood producing bone marrow cells are among human tissues of rapid growth that provide for the attrition of their end-of-the-line constituents and, their spontaneous differentiation is actually pre-determined, not manipulated and, or induced. Same applies to skin and biological cardiac valves. Corneal transplants, ligaments, bone and cartilage grafts should be considered developed tissues with full functional capability like the lung, pancreas, kidney, liver and heart. Therefore, they fall outside of the frame that define regenerative therapies.
To create tissue scaffolds whose function would approximate the biological extracellular matrix (ECM) paradigm changes in understanding, design and fabrication methods must be made. In regard to structures build with prosthetic biomaterials, most work has been within the macroscopic or microscopic realm. Technologies such as fabrication methods, biomechanical performance and quality assurance apply largely to the visible size range with or without the assistance of optical magnification. The optimal range of most technologies used in the medical device industry is at the sub-millimeter and micron level as defined by industrial manufacturing tolerances. This may be adequate for current device technology but insufficient for sub-micron and nanometer detail.
While pharmacological agents are designed focusing on molecular interactions with cell membrane receptors and other nanoscopic size targets, implantable biomaterials interaction with biological tissues are usually assessed by histopathological effects such as mechanical injury and surface boundary phenomena such as thrombogenicity and inflammation. The focus should shift from the micron to the nanometer world for the assessment of material interactions with living tissues.
It is known, for example, that current commercial biomaterials, such as those used to fabricated vascular stents, have high degrees of surface irregularities at the microscopic level and multiple foreign material inclusions, such as carbide inclusions or residual from process lubricants.
As progress is made into a smaller dimensional world, each step down creates new challenges. This is already evident in the quality assurance and lower tolerance levels of implantable microdevices, requiring increasingly sophisticated measuring equipment and computer data management to cope with the ever increasing design complexity and volume of QA data.
The commitment to design and manufacture at the nano-scale is neither simple nor economically efficient in the present reality of the medical device industry. However, efforts must be undertaken to change current simplistic approaches to new devices. This is not easy because approved devices are currently considered safe and effective by older stablished criteria. However, adherence to these criteria is a hinderance to progression to more sophisticated devices and even unforeseen new applications.
A PEEK into Cellular Response to Engineered Surfaces
Controlled nanofabrication on artificial surfaces allows for micro-engineering of prosthetic surfaces in a manner that is highly controllable. Working on micro-engineering of the surface of implantable vascular stents materials new techniques for fabrication of high definition microgrooves have been developed (38). The goal was to increase the migration speed and influence growth direction of human aortic endothelial cells to accelerate colonization and therefore positively influence the prosthetic healing process. Engineered micro-grooves have been made that are within the size range of vascular endothelial cells (EC). An effort was made to maintain the features definition within few hundred nanometers. As technology moved from abrasive to laser, to photolithography manufacturing techniques it was quickly realized that the limiting factor was the materials being working with. The engineered features on the prosthetic surface that were initially used were within the size range of currently accepted surface topography variability. This implied that to fabricate those features with consistent regularity the putative background surface had to be chemically and topographically more uniform. The result of trying many iterations of fabrication techniques and material, revealed the importance of the edge definition of the features. In other words, the cellular response increased with control of feature regularity at submicroscopic level. Migrating endothelial cells are sensitive to surface topography whether this is by their physical presence or by redistribution of surface adhesive proteins. Un-interrupted outer edges and inner corners act as guides for the EC lamellipodia and other migrating cell filopodia to follow, pulling the rest of the cell behind.
This guidance effect is lost as the feature edge gets interrupted. Thereby, the importance of high-definition longitudinal feature continuity. Guidance effects can be an approach to correctly locate cells within a matrix whether they be endothelial, epithelial, parenchymal or osteoblastic cellular arrays, or attempts at neuroaxonal reconnection. This pursuit necessitates the development of new biomaterials to allow fabrication in the sub-microscopic range. By achieving nanoscopic controlled features a surprising and unexpected change in cellular response from random to consistent was observed. Higher quality levels of material composition defined as topographical and chemical homogeneity and enhanced robustness provide an adequate canvass for new, high-definition designs and fabrication. Currently, the metal alloys used for most implantable devices have marked crystal size variability and carry lattice defects and impurities in the form of inclusions from fabrication residues (39). These materials cannot be used to make device features with sub-microscopic detail. This is also important with device features smaller than the size of a single crystal or inclusion deposit in current bio-alloys as corrosion and fatigue resistance quickly diminish with miniaturization.
As prosthetic scaffolds evolve toward microscopic designs, the architecture of the PECM to favor cell attachment mechanisms, fluids exchange, large and small molecular movement, immune cell migration and apoptotic cell debris disposal (
Current devices are largely made by top-down or reductive manufacturing. These classical technologies rely on extensive and skilled hand labor, produce waste and suffer from relatively large product variability and rejection rates. Reductive manufacturing commonly involves a complicated series of steps, each one leaving footprints that affect the surface chemical and topographical homogeneity. As complex microscopic and submicroscopic constructs are considered, these methods may no longer be useful. Human manual processing will be replaced by automated manufacturing and new technologies uncommon in the medical device industry today will be common place. This is the case for physical vapor deposition (PVD) of metals and alloys, ceramics and polymers and extensive robotic use of photolithography and femto-second lasers.
Additive PVD achieves an orderly deposition of metal or pseudometal atoms from a high energy plasma.
The enabling technologies are today more ubiquitous in energy and electronics fields than in medical devices. Most importantly, quality assurance and control requirements will exponentially increase with complex, smaller devices, requiring larger computer data processing. The use of machine learning and artificial intelligence (AI) will allow for an increase in the role of high-power computers in all aspects of new devices from complex designs, to manufacturing, to quality control and data handling. The new manufacturing facilities will likely have smaller physical plants, fewer operators and substantial computer involvement.
The evolution of technology toward fabricating features dimensionally closer to the size of cells is inevitable but the technology will change to the point it does no longer resemble what is a typical medical device company. The regulatory agencies may need to adapt to the change by shifting the emphasis from device-centered to method-centered, thereby regulating the certification of processes that allow for flexibly changing design and eventually facilitating personalized device manufacturing.
In some ways, future creation of new devices will resemble new drug design and manufacturing that focus on subcellular targets. Surface chemistry at device surfaces as well as surface topography at the molecular level and its effect on and interaction with cells and molecules must be considered. This calls for a fundamental change in the way prosthetic constructs and design will address the molecular make-up of the biological environment rather than using the current adaptive/adoptive approach. In other words, no longer available materials and technologies will be borrowed from other fields, based on their procure-ability, practicality and implementation by trial and error. Rather, materials and methods will be tailor-made to fit applications.
Eventually, fabrication of devices will be chemical-based. Partly in-vitro and partly in-vivo, the assembly of microscopic components will be managed by complementary reactants strategically placed in nanoblocks with geometrical growth capability. Architectural plasticity will be managed by computer control of reactants acting as chemical triggers of hierarchical in-vivo growth. Carbon nanoparticles maybe possible candidates for their material properties and the ability for chemical derivatization. However fascinating, chemical based in-vivo prosthetic build-up is farther in the future that the possibilities presently at hand. (40).
What will be the next big step in the discovery and application of organ replacements is hard to predict as so many factors influence these evolutionary trends. However, some pieces of this puzzle are already in place providing a glimpse of what may be the next big thing in this area. Starting with prosthetic biomaterials, the use of AI to create super-materials may eliminate what is today a long and tedious process to arrive at products with ideal properties by trial and error. Computers will tell us the ideal combination of components with perfect stoichiometry for optimized properties for a given application (41). Superalloys will be made overnight in vacuum plasma reactors rather than in foundry furnaces. Manufacturing labor, waste and rejection of out of specification product will be almost eliminated.
Progress in understanding tissue transmission of electrical and electromagnetic energy (42) is already influencing implantable technologies like cardiac pacing, in the application of addressable lead-less pacemakers (43). Also, it should aid in new developments in neuroscience technology to successfully establish connectivity between electrical impulses originated in the brain and external actuators, or from impulses generated extracorporeally to elicit specific neuronal excitation (44). This will open up long-awaited opportunities for rehabilitating victims of traumatic and degenerative brain-spinal disfunction resulting in enabled motor function and speech. It is not hard to imagine that if brain connectivity is finally conquered, vision and auditory functions can also be restored. Furthermore, with current available technologies is easy to imagine enhanced sensory functions as high definition, infrared and ultra-low light vision.
This same principal applies to all sensory organs, such as enhancing or replacing pathways for touch, taste, smell, hearing or the like. Following this line of thought is also conceivable that radio communications allowed by an effective computer brain-interface will provide access of just about all the telecommunications and internet connectivity that most human beings presently enjoy by mere conscious thinking.
The improvement in quality of life that many prosthetic devices offer to the aging population are amazing. This is mainly by alleviating life-style limiting conditions that were previously ostracizing and, or debilitating and contributed to the inevitable decline of old age.
However, more significant is the progressive disappearance of the prosthetic stigma. The ancient prototypical wooden leg, ear horn and the gold tooth have given place to high tech limb prosthesis and imperceptible tooth implants. Just as important as the functional benefit they provide, is the decrease of real or perceived social isolation imposed by the need of using odd prosthetic replacements or aids. It can easily be imagine that if enhanced vision and other sensory functions become available, the level of acceptance will be even higher or even be replaced by a sense of pride in the user. Electro-mechanically assisted exo-skeletal frames are commonplace in assembly lines to assist high effort operations (45). It is not inconceivable that they will replace the traditional wheel-chair, particularly if they can be operated by violative brain command.
In other words, the lines between handicapped and non-handicapped people may start blurring out and many of these life-facilitating and life-enhancing prosthetic assists may have profound influences in society.
Academic Press, 2004
Improving outcomes with a multidisciplinary approach. J Multidiscip Health 2018; 11:63
The present application is claims priority to co-pending U.S. Patent Application Ser. No. 63/192,531, filed May 24, 2021.
| Number | Date | Country | |
|---|---|---|---|
| 63192531 | May 2021 | US |
