IPC分类号：
B22F10/38 | A61L27/16 | A61L27/56 | C12M1/00 | C12M3/00 | B22F10/14 | B22F10/85 | B29C64/165 | B29C64/393 | B33Y10/00 | B33Y50/02 | B33Y80/00
当前申请(专利权)人：
OHIO STATE INNOVATION FOUNDATION
原始申请(专利权)人：
OHIO STATE INNOVATION FOUNDATION
当前申请(专利权)人地址：
1524 NORTH HIGH STREET, 43201, COLUMBUS, OHIO
发明人：
PADILLA, HERNAN LARA | DEAN, DAVID | RODRIGUEZ, CIRO
摘要：
The present disclosure describes additive manufacturing methods, in particular methods for optimizing the manufacture of objects by three-dimensional printing processes. Also provided are bioreactors as well as methods of using thereof.
技术问题语段：
The technical problem addressed in this patent text is the need for better approaches to repair bone defects, which can occur due to trauma, birth defects, injuries, and other factors. Current bone grafting techniques have limitations, such as complications and poor outcomes, and there is a need for alternative approaches. The text discusses the use of bone graft substitutes and scaffolds to aid in regenerating bone tissue and expand the use of allografting.
技术功效语段：
This patent discusses methods for improving the process of printing three-dimensional objects using 3D printing. The methods help reduce failures during fabrication, which can occur due to stress, weak materials, or other factors. The methods involve altering various process parameters, such as changing the orientation of the build, selecting a different additive manufacturing device, or modifying structural elements of the build. These methods also involve separating the layer of the object from the basement plate to increase its strength and stability during the printing process. Overall, the methods described in this patent can enhance the production of three-dimensional objects using 3D printing techniques.
权利要求：
1. A method for optimizing an additive manufacturing process for the production of a three-dimensional object using an additive manufacturing device, the method comprising:
evaluating inter-layer green strength between two layers of a build;
evaluating forces acting on the build during the additive manufacturing process;
comparing the inter-layer green strength to the forces acting on the build; and
altering one or more process parameters of the additive manufacturing process when the forces acting on the build are greater than the inter-layer green strength.
2. The method of claim 1, wherein the forces acting on the build comprise one or more of stretching of the build, torsion of the build, shrinking of the build, compression of the build, elongation of the build, adhesion of the build, or any combination thereof.
3. The method of claim 1, wherein altering one or more process parameters comprises changing the orientation of the build with respect to the additive manufacturing device.
4. The method of claim 3, wherein changing the orientation of the build comprises selecting a new orientation wherein the forces acting on the build are less than the inter-layer green strength.
5. The method of claim 1, wherein altering one or more process parameters comprises selecting a different additive manufacturing device for production of the three-dimensional object.
6. The method of claim 1, wherein altering one or more process parameters comprises modifying structural elements of the build.
7. The method of claim 6, wherein modifying structural elements of the build comprises increasing cross-sectional overlap between the two layers of the build.
8. The method of claim 6, wherein modifying structural elements of the build increases the inter-layer green strength such that it is greater than the forces acting on the build during the additive manufacturing process.
9. The method of claim 1, wherein altering one or more process parameters comprises altering a material used to form the build during the additive manufacturing process.
10. The method of claim 9, wherein the material used to form the build during the additive manufacturing process comprises a light polymerizable material, and wherein altering the material comprises selecting a different light polymerizable material.
11. The method of claim 10, wherein the different light polymerizable material exhibits different rheological properties than the material used to form the build during the additive manufacturing process.
12. The method of claim 1, wherein the material used to form the build during the additive manufacturing process comprises a light polymerizable material, and wherein altering one or more process parameters comprises altering incident energy applied to the light polymerizable material to induce crosslinking.
13. The method of claim 12, wherein altering incident energy comprises varying a wavelength of incident light, varying an intensity of incident light, varying a duration of incident light, or any combination thereof.
14. The method of claim 1, wherein evaluating inter-layer green strength for the two layers of the build comprises measuring the inter-layer green strength.
15. The method of claim 1, wherein evaluating inter-layer green strength for the two layers of the build comprises modeling the inter-layer green strength.
16. The method of claim 15, wherein modeling the inter-layer green strength comprises computational modeling.
17. The method of claim 1, wherein modeling the inter-layer green strength comprises measuring the inter-layer green strength from a model of the build.
18. The method of claim 1, wherein evaluating forces acting on the build comprises measuring forces acting on the build during the manufacturing process.
19. The method of claim 1, wherein evaluating forces acting on the build comprises modeling the forces acting on the build.
20. The method of claim 19, wherein modeling the forces acting on the build comprises computation modeling.
21. The method of claim 19, wherein modeling the forces acting on the build comprises measuring forces acting on a model of the build.
22. The method of claim 21, wherein the model of the build further comprises internal force sensors.
23. A method for optimizing the manufacture of a layer of an object using an additive manufacturing process, wherein the object is subjected to one or more forces during its manufacture, the method comprising:
(a) determining the inter-layer green strength of the layer;
(b) determining each quantity of force applied to the layer as the object is built layer-by-layer;
(c) comparing the inter-layer green strength to each quantity of force experience by the layer at any point of the manufacturing process;
wherein if a quantity of force applied is greater than the inter-layer green strength, the design of the structure of the layer is modified to increase cross-sectional overlap of layer with one or more adjacent layers.
24. A method for optimizing the manufacture of a layer of an object using an additive manufacturing process, wherein the object is composed of a material, and wherein the object is subjected to one or more forces during its manufacture, the method comprising:
(a) determining the inter-layer green strength of the layer;
(b) determining each quantity of force applied to the layer as the object is built layer-by-layer;
(c) comparing the inter-layer green strength to each quantity of force experience by the layer at any point of the manufacturing process;
wherein if a quantity of force applied is greater than the inter-layer green strength, the manufacture of the object is modified to replace the material from which it is composed with a second material that has an inter-layer green strength greater than any quantity of force applied to the layer.
25-59. (canceled)
技术领域：
[0002]This disclosure related to additive manufacturing methods, and more particularly to methods for optimizing three-dimensional printing processes. Also described are bioreactor designs as well as methods of using thereof.
背景技术：
[0003]Bones provide several functions, from load-bearing, structural integrity and protection to hematopoietic and immunological cell creation. The types of bone have been classified according to their functions, shapes and sizes (“Atlas of Human Anatomy—6th Edition” n.d.). The main two components of mineralized tissue are cortical bone and cancellous bone. Cortical bone is also called “compact bone” as it is much denser and forms the hard exterior of bones. Its main function is mechanical, supporting and/or protecting organs. It also serves as mineral (especially calcium) storage, comprising about 80% of the total bone mass in an adult. Cancellous bone is also known as trabecular of spongy bone tissue, and is an open cell porous network, which makes it ideal for metabolic activities. It is rich in bone marrow and hematopoietic stem cells, and blood vessels. It comprises about 20% of the adult human's total bone mass. Cancellous bone is typically found at the end of long bones, near joints and within the interior.
[0004]In general, the bone is regarded as a tough matrix that is mineralized that gives it its strength. The matrix is about 30% of the bone and over 90% is based on collagen fibers, the rest is a gel-like substance in the extracellular space that comprises of all components of the extracellular matrix. The remaining 70% of the bone is comprised of minerals and salts that provide strength (“Guyton and Hall Textbook of Medical Physiology—12th Edition” n.d.). Minerals in bone are mostly calcium phosphate in the form of hydroxyapatite. All these are created by bone-forming cells, known as osteoblasts that produce mostly type 1 collagen. Osteoblasts secretes these collagen fibers all around themselves and then they deposit calcium phosphate. This new bone is called osteoid. Once the Osteoblast is trapped, it is known as an Osteocyte. Osteoclasts are large cells that resorb the bone, in a never-ending remodeling that is balanced by osteoblasts, and that are also play an important role in calcium homeostasis (“Guyton and Hall Textbook of Medical Physiology—12th Edition” n.d.). The key regulator of osteoblast and osteoclast activity is mechanical strain, such as when there's increased load, the bone will adapt and add new bone in response to it or remove in response to unloading (Burr, Robling, and Turner 2002).
[0005]Bone defects are a common occurrence in life that come from several etiologies, such as high-energy trauma, birth defects, injuries, osteoporosis derived pathological fractures, gunshot trauma, iatrogenic resection of infected or neoplastic bone lesions and a whole myriad of causes that can affect patients in the long term. These defects are dependent on the size, place, and type of bone in which they occur. The ability to repair them depend on the available stock for bone grafting. Critical size segmental defects are generally considered as defects that will never heal on their own without any intervention by a surgeon. Bone grafting requires placing plates, screws and guides, and sometimes other measures. Critical size defects are the most difficult to treat, and prior to the advent of complex reconstructive surgical procedures, most of them ended up in amputation or permanent functional deficits. Unfortunately, there are no artificial bone grafts that can restore full functionality and that can be well tolerated by the patients undergoing the approach (Gugala, Lindsey, and Gogolewski 2007). Because life expectancy continues to increase, these cases are rising in occurrence, being the most demanding spinal fusion and nonunion fractures (Kinaci, Neuhaus, and Ring 2014).
[0006]Today, the use of bone grafting remains the standard-of-cap in the clinic for longbone segmental defects, but the results are far from perfect. It is estimated that every year around 1 million bone allografts are used (Ng 2012). They come with complications that are way too common, from rejection to infection, take too long to heal, they never approach full range of function and some poor outcomes in general. These interventions include the more common treatment using cancellous bone grafting, as well as cortical allografts, vascularized bone grafts, and distraction osteogenesis (DeCoster et al. 2004). The major shortcomings of these interventions are due to several factors, being the most important lack of structural integrity and high failure in large bone defects due to rapid graft resorption. They come with the added restrictions that are limited availability and morbidity of the donor site (Banic and Hertel 1993).
[0007]These problems have pushed practice to look for other approaches, being bone graft substitutes a huge area of research. These strides have focused on osteogenic options such as bone marrow aspirate and blood concentration to remove platelet-rich plasma, as well as osteoconductive fillers, comprising ceramics, cements, and polymers (synthetic or natural) as well as addition of osteoinductive molecules like growth factors and cytokines. Tissue engineering has tested several constructs and as of today, the most potent osteoinductive additions are demineralized bone matrix and recombinant human morphogenetic proteins approved for use in bone deficiencies (Gugala, Lindsey, and Gogolewski 2007).
[0008]It is important to mention that even though autologous and allogenic bone grafts are being used, they often require a frame and a vascularization (e.g muscle and/or arterial graft) to allow for tissue to be regenerated, and that is the common focus on research today. The use of a scaffold in combination with bone substitutes and/or aggregates may allow better results and expand the use of allografting as we know it or even supplement it. The push in today's biomaterials' research has focused on implants that aide in the structure, vascularization, and grow factors for implanted bone grafts (Griffin et al. 2015). The search for a successful bone scaffold seeks three main properties: osteoconditivity, osteointegration and osteoinductivity. Cancellous grafts have mild-to moderate osteoconductive properties, mild osteoinductive ones, and practically no structural strength. Cortical bone grafts provide great strength and stability but are very poor in osteoinduction (Giannoudis, Dinopoulos, and Tsiridis 2005).
[0009]The generation of a “artificial bone” substitute to repair skeletal defects has been the concern of mankind for thousands of years. The substitution of bone parts can be considered as early efforts to use biomaterials in reconstructive medicine. For instance, diversity of methods has been proposed for cranium reconstruction from prehistory to modern medicine attests to the engaging nature of the problem (Abhay and Haines 1997). During the last decades, this concept became feasible and has been recently introduced in medicine. Tissue engineering and regenerative medicine are terms for the field in biomedicine that deal with the transformation of these fundamental ideas to practical approaches (Meyer 2009).
[0010]Current approaches to skeletal reconstructive surgery use biomaterials, autografts or allografts, although restrictions on all these techniques exist. These restrictions include donor site morbidity, pain and donor shortage for autografts, immunological rejection, and the risk of transmitting infectious diseases (Laurencin, Khan, and El-Amin 2006). Many artificial tissue substitutes containing metals, ceramics, and polymers were introduced to maintain skeletal function. However, each material has specific disadvantages, and none of these can perfectly substitute for autografts in current clinical practice. The use of biomaterials is a common treatment option in clinical practice. One reason for the priority of tissue grafts over nonliving biomaterials is that they contain cells and tissue-inducing substances, thereby possessing biological plasticity (Meyer et al. 2009). Research is currently in progress to develop cell-containing hybrid materials and to create replacements for bone tissue that are bioactive after implantation, imparting physiological functions as well as structure to the tissue or organ damaged by disease or trauma.
Additive manufacturing technologies have unlocked new possibilities for bone tissue engineering (BTE). Long-term regeneration of regular anatomic structure, shape, and function is clinically essential after bone trauma, tumor, infection, nonunion after fracture, or congenital abnormality. Additive manufacturing could provide the ability to print bone substitute materials with controlled chemistry, shape, porosity, and topography, thus allowing printing of personalized bone grafts customized to the patient and the specific clinical condition (Jariwala et al. 2015).
[0011]While there is no clinically available “bone substitute”, potentially promising process for the generation of a synthetic bone graft has been suggested by (Rodriguez, Lara-Padilla, and Dean 2018). Briefly, based on the type of the bone defect, the initial point will be synthetic bone graft design. At the next stage, a scaffold is manufactured. The subsequent stage involves combining cells with the scaffold to constitute a synthetic bone graft. Growth factors may be added at this stage. In some cases, the scaffold alone (cell-free scaffold) is used as the graft. Finally, the synthetic bone graft is implanted into the bone defect to promote the regeneration of new tissue.
[0012]There is a clear need for novel methods and apparatuses for the manufacture of porous scaffolds for use in tissue engineering applications. Further, while methods and apparatuses for the manufacture of porous scaffolds can find use in tissue engineering applications, these insights may more broadly inform additive manufacturing processes in general.
发明内容：
[0013]The present disclosure provides methods for optimizing the manufacture of three-dimensional objects (e.g., including situation-specific external shapes with porous internal surfaces) using three-dimensional printing processes. Methods are provided that help reduce the failure rate during manufacturing of these objects by 3D printing processes, an issue of significance due to the high tendency to fail during fabrication either due to stress concentrations in small regions, the use of relatively weak materials, or both.
[0014]Thus in one aspect, a method for optimizing an additive manufacturing process for the production of a three-dimensional object using an additive manufacturing device is provided, the method comprising:
[0015]evaluating inter-layer green strength for two layers of a build;
[0016]evaluating forces acting on the build during the additive manufacturing process;
[0017]comparing the inter-layer green strength to the forces acting on the build; and
[0018]altering one or more process parameters of the additive manufacturing process when the forces acting on the build are greater than the inter-layer green strength.
[0019]In some embodiment, the forces acting on the build comprise one or more of stretching of the build, torsion of the build (e.g., on the part while it is being built), shrinking of the build, compression of the build, elongation of the build, adhesion of the build, or any combination thereof. In some embodiments, altering one or more process parameters comprises changing the orientation of the build with respect to the additive manufacturing device. In some embodiments, changing the orientation of the build comprises selecting a new orientation wherein the forces acting on the build are less than the inter-layer green strength. In some embodiments, altering one or more process parameters comprises selecting a different additive manufacturing device for production of the three-dimensional object. In some embodiments, altering one or more process parameters comprises modifying structural elements of the build. In some embodiments, modifying structural elements of the build comprises increasing cross-sectional overlap between the two layers of the build. In some embodiments, modifying structural elements of the build increases the inter-layer green strength such that it is greater than the forces acting on the build during the additive manufacturing process.
[0020]In some embodiments, wherein altering one or more process parameters comprises altering a material used to form the build during the additive manufacturing process. the material used to form the build during the additive manufacturing process comprises a light polymerizable material, and wherein altering the material comprises selecting a different light polymerizable material. In some embodiments, the different light polymerizable material exhibits different rheological properties than the material used to form the build during the additive manufacturing process. In some embodiments, the material used to form the build during the additive manufacturing process comprises a light polymerizable material, and wherein altering one or more process parameters comprises altering incident energy applied to the light polymerizable material to induce crosslinking. In some embodiments, altering incident energy comprises varying a wavelength of incident light, varying an intensity of incident light, varying a duration of incident light, or any combination thereof.
[0021]In some embodiments, evaluating inter-layer green strength for two layers of the build comprises measuring the inter-layer green strength. evaluating inter-layer green strength for two layers of the build comprises modeling the inter-layer green strength. In some embodiments, modeling the inter-layer green strength comprises computational modeling. In some embodiments, modeling the inter-layer green strength comprises measuring the inter-layer green strength of a model of the build.
[0022]In some embodiments, evaluating forces acting on the build comprises measuring forces acting on the build during the manufacturing process. In some embodiments, evaluating forces acting on the build comprises modeling the forces acting on the build. In some embodiments, modeling the forces acting on the build comprises computation modeling. In some embodiments, modeling the forces acting on the build comprises measuring forces acting on a model of the build. In some embodiments, the model of the build further comprises internal force sensors.
[0023]In another aspect, a method for optimizing the manufacture of a layer of an object using an additive manufacturing process is provided, wherein the object is subjected to one or more forces during its manufacture, the method comprising:
[0024](a) determining the inter-layer green strength of the layer;
[0025](b) determining each quantity of force applied to the layer as the object is built layer-by-layer;
[0026](c) comparing the inter-layer green strength to each quantity of force experience by the layer at any point of the manufacturing process;
[0027]wherein if a quantity of force applied is greater than the inter-layer green strength, the design of the structure of the layer is modified to increase cross-sectional overlap of layer with one or more adjacent layers.
[0028]In another aspect, a method for optimizing the manufacture of a layer of an object using an additive manufacturing process, wherein the object is composed of a material, and wherein the object is subjected to one or more forces during its manufacture, the method comprising:
[0029](a) determining the inter-layer green strength of the layer;
[0030](b) determining each quantity of force applied to the layer as the object is built layer-by-layer;
[0031](c) comparing the inter-layer green strength to each quantity of force experience by the layer at any point of the manufacturing process;
[0032]wherein if a quantity of force applied is greater than the inter-layer green strength, the manufacture of the object is modified to replace the material from which it is composed with a second material that has an inter-layer green strength greater than any quantity of force applied to the layer.
[0033]In another aspect, a method for selecting between a first orientation and a second orientation for manufacturing an object using an additive manufacturing process, wherein the object is manufactured in the first orientation out of a first plurality of layers and in the second orientation out of a second plurality of layers, and wherein the object is subjected to one or more forces during its manufacture, the method comprising:
[0034](a) determining the ratio of an average of the force applied to each layer of the first plurality of layers to the average of the inter-layer green strength of each layer of the first plurality of layers to provide a first force to green strength ratio;
[0035](b) determining ratio of an average of the force applied to each layer of the second plurality of layers to the average of the inter-layer green strength of each layer of the second plurality of layers to provide a second force to green strength ratio;
[0036](c) comparing the first force to green strength ratio to the second force to green strength ratio; and
[0037](d) selecting the orientation for manufacture that is associated with the lesser of the first force to green strength ratio and the second force to green strength ratio.
[0038]In some embodiments, the additive manufacturing process is selected from a material extrusion process, a powder bed fusion process, a binder jetting process, a stereolithography process, a computed axial lithography process, a liquid additive (e.g., hydrogel bioprinting, hydrogel bioassembly, or photocrosslinked hydrogel) manufacturing process, or a directed energy deposition (DED) process. In some embodiments, the additive manufacturing process is continuous digital processing (cDLP).
[0039]In some embodiments, the force applied to the object is a separation force.
[0040]In some embodiments, the object is manufactured from a resin composition comprising a liquid light-curable material and a photoinitiator.
[0041]In some embodiments, the separation force of a layer is determined by:
[0042](a) providing an additive manufacturing apparatus including a Digital Micromirror Device (DMD) that is part of a cDLP 3D printer, a transparent or translucent basement plate, and a build plate operatively coupled to a force sensor;
[0043](b) depositing an amount of the resin composition above the basement plate;
[0044](c) activating the DMD to expose a portion of the resin composition to light to at least partially crosslink the liquid light-curable polymerizable material therein to form the layer of the three-dimensional object;
[0045](d) actuating the build plate or the basement plate to increase the distance between the build plate and the basement plate such that the layer of the three-dimensional object is separated from the basement plate;
[0046](e) measuring the separation force required to separate the layer of the three-dimensional object from the basement plate with the force sensor during step (d).
[0047]In some embodiments, the inter-layer green strength of the material is determined by:
[0048](a) providing an additive manufacturing apparatus including a Digital Micromirror Device (DMD), a transparent or translucent basement plate, and a build plate operatively coupled to a force sensor;
[0049](b) depositing an amount of the resin composition above the basement plate;
[0050](c) actuating the DMD to expose a portion of the resin composition to light to at least partially crosslink the liquid light-curable polymerizable material therein to form the first layer having a first cross-sectional area;
[0051](d) actuating the build plate or the transparent or translucent basement plate to increase the distance between the build plate and the basement plate to separate the first layer from the basement plate;
[0052](e) actuating the DMD to expose an additional portion of the resin composition to light to at least partially crosslink the liquid light-curable polymerizable material to form a second layer having a second cross-sectional area and to at least partially overcure at least some of the first layer to the second layer to cause at least some interlayer binding between the first layer and the second layer, wherein the second cross-sectional area is greater than the first cross-section area;
[0053](f) actuating the build plate or the basement plate to separate the second from the basement plate, wherein the force sensor measures the separation force required to separate the second layer from the basement plate;
[0054](g) measuring the separation force required to separate the second layer from the basement plate with the force sensor during step (f);
[0055](h) repeating steps (e), (f) and (g) to form one or more additional layers have one or more additional cross-sectional areas until there is a failure of the interlayer binding of any two of the layers upon actuation of the build plate or basement plate, wherein each additional cross-sectional area is greater than the cross-sectional area of the previous layer;
[0056](i) calculating the inter-layer green strength by dividing the separation force measured for the most recent additional layer manufactured during step (h) upon failure of interlayer binding by the additional cross-sectional area of the most recent additional layer.
[0057]In another aspect, a method for optimizing the manufacture of a layer of an object using continuous digital light processing (cDLP), wherein the layer has a cross-sectional area, and wherein the object is composed of a material manufactured from a resin composition comprising a liquid light-curable polymer and a photoinitiator, the method comprising:
[0058](a) measuring the separation force for a test layer having substantially the same cross-sectional area as the layer of the three-dimensional object using the method of claim 30;
[0059](b) measuring the inter-layer green strength of the material using the method of claim 31;
[0060](c) calculating the probability of structural failure of the layer by comparing the separation force of the test layer with the inter-layer green force of the material, wherein if the separation force of the test layer is greater than the inter-layer green force of the material, the resin composition is modified.
[0061]In another aspect, a method for optimizing the manufacture of a layer of a three-dimensional object using continuous digital light processing (cDLP), wherein the layer has a cross-sectional area, and wherein the object is composed of a material manufactured from a resin composition comprising a liquid light-curable polymer and a photoinitiator, the method comprising:
[0062](a) measuring the separation force for a test layer having substantially the same cross-sectional area as the layer of the three-dimensional object using the method of claim 14;
[0063](b) measuring the inter-layer green strength of the material using the method of claim 15;
[0064](c) calculating the probability of structural failure of the layer by comparing the separation force of the test layer with the inter-layer green force of the material, wherein if the separation force of the test layer is greater than the inter-layer green force of the material, the structure of the layer of the three-dimensional object such that cross-sectional overlap between the layer and one or more adjacent layers is increased.
[0065]In some embodiments, the three-dimensional object is a tissue engineering scaffold. In some embodiments, the produced scaffold includes pores having openings with diameters in the range of 50 to 1600 micrometers. In some embodiments, the scaffold includes pores having a substantially cylindrical structure. In some embodiments, the scaffold includes pores having a substantially oblique structure.
[0066]In some embodiments, the liquid light-polymerizable material has a molecular weight of approximately 4,000 Daltons or less. In some embodiments, the liquid light-polymerizable material includes poly(propylene fumarate) (PPF). In some embodiments, the resin composition further comprises a dye. In some embodiments, the ratio of dye to photoinitiator is selected to control the depth of penetration of light. In some embodiments, the dye includes 2-hydroxy-4-methoxybenzophenone. In some embodiments, the photoinitiator includes bis(2,4,6-trimethylbenzoyl)phenylphosphine oxide (BAPO). In some embodiments, the photoinitiator includes bis[2,6-difluoro-3-(1-hydroxypyrrol-1-yl)phenyl]titanocene. In some embodiments, the resin composition further comprises a solvent. In some embodiments, the resin composition further comprises diethyl fumarate (DEF).
[0067]In another aspect, a direct perfusion bioreactor system for three-dimensional tissue culture of a tissue engineering scaffold is provided comprising:
[0068]At least one perfusion chamber for housing the tissue engineering scaffold having a chamber flow inlet and a chamber flow outlet;
[0069]An in-line peristaltic pump having a pump flow inlet and a pump flow outlet;
[0070]a culture medium reservoir having a reservoir flow inlet and a reservoir flow outlet;
[0071]wherein the pump flow outlet is in fluid communication with the chamber flow inlet;
[0072]wherein the chamber flow outlet is in fluid communication with the reservoir flow inlet; and
[0073]wherein the reservoir flow outlet is in fluid communication with the pump flow inlet.
[0074]In some embodiments, the perfusion chamber and culture medium reservoir are housed within an incubator. In some embodiments, the peristaltic pump is housed outside an incubator. In some embodiments, the perfusion chamber is composed of a disposable material. In some embodiments, the perfusion chamber is a syringe. In some embodiments, the perfusion chamber is composed of soft tubing. In some embodiments, the soft tubing is subjected to an external pressure to conform the tubing to the shape of the tissue engineering scaffold. In some embodiments, the bioreactor system comprises two or more perfusion chambers. In some embodiments, the pump flow outlet is in fluid communication with the chamber flow inlet by plastic tubing. In some embodiments, the chamber flow outlet is in fluid communication with the reservoir flow inlet by plastic tubing. In some embodiments, the reservoir flow outlet is in fluid communication with the pump flow inlet by plastic tubing. In some embodiments, the tissue engineering scaffold is held in place within the at least one perfusion chamber by a pair of conical springs.
[0075]The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and the drawings, and from the claims.
具体实施方式：
[0094]Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. The following definitions are provided for the full understanding of the terms used in the specification.
[0095]As used in the specification and claims, the singular form “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an agent” includes a plurality of agents, including mixtures thereof.
[0096]As used herein, the terms “may,”“optionally,” and “may optionally” are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation “may include an excipient” is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient.
[0097]“Breaking load” as used herein refers to the load applied at some point to a component or structure which leads to fracture.
[0098]“Build” as used herein refers to a 3-dimensional object being formed by a layer-by-layer additive manufacturing process.
[0099]“Burn-in layers” as used herein refers to the early layers needed to stick the printed part to the build platform. In some embodiments, the burn-in layers need 2×-4× times higher cure time than normal layers.
[0100]“Cure depth” refers to the thickness of a single layer of a photo resin exposed to a certain amount of exposure time.
[0101]“Dye-initiator” as used herein refers to a compound used to ensure accurate control of the depth of polymerization.
[0102]“Dynamic viscosity” as used herein refers to the ratio, for a fluid, of the viscous shear stress to the rate of strain. It may vary with temperature and pressure.
[0103]“Exposure time” as used herein refers to the amount of time used to project a digital mask using light to cure a layer during the 3D printing process with cDLP.
[0104]“Green strength” or “overall green strength” is a general term that comprises all the mechanical properties of the light-cured part including modulus, strain, strength, hardness, and layer-to-layer adhesion. It must be sufficiently large that a part will not distort before or during the final postcure.
[0105]“Growth factors” as used herein refers to a diverse group of proteins that are important in the regulation of cell proliferation (growth) and differentiation.
[0106]“Inter-layer green strength” or “Layer stitching” or “Inter-layer binding” as used herein refers to a grade of strength as an indication of crosslinking density during the exposure time of each layer during a layer-by-layer additive manufacturing process. In some cases, the additive manufacturing process can be continuous Digital Light Processing (cDLP).
[0107]“Layer thickness” as used herein is the nominal thickness of a single layer obtained in the cure depth experiment.
[0108]“Overcuring” as described herein is the thickness of the layer minus step size.
[0109]“Photoinitiator” as described herein is a chemical that undergoes a photoreaction on absorption of light, induces polymerization.
[0110]“Resin” refers to a viscous substance of organic or synthetic origin that is typically convertible into a polymer.
[0111]“Separation velocity” refers to the velocity of the build elevation as it pulls away from the basement.
[0112]“Solvent” as used herein refers to a compound used to reduce the viscosity of photopolymer resins.
[0113]“Step size” refers to the gap between the bottom part of basement (vat) and the last cured layer.
[0114]The terms additive manufacturing process and 3-d printing are used herein synonymously.
Additive Manufacturing Processes
[0115]Additive manufacturing comprises building a three-dimensional object from a computer-aided design (CAD) model, usually by successively adding material layer by layer. The term covers a variety of processes in which material is joined or solidified under computer control to create a three-dimensional object, with material being added together (such as liquid molecules or powder grains being fused together), typically layer by layer. 3D printing processes typically comprise the steps of modeling the object on a computer, printing using any of the processes described herein, and finishing the product as deemed necessary for the particular application.
[0116]3D printable models may be created with a computer-aided design (CAD) package, via a 3D scanner, or by a plain digital camera and photogrammetry software. 3D printed models created with CAD result in reduced errors and can be corrected before printing, allowing verification in the design of the object before it is printed. 3D scanning is a process of collecting data on the shape and appearance of a real object, creating a digital model based on it.
[0117]CAD models can be saved in the stereolithography (STL) file format, a de factor CAD file format for additive manufacturing that stores data based on triangulations of the surface of CAD models. STL is not tailored for additive manufacturing because it generates large file sizes of topology optimized parts and lattice structures due to the large number of surfaces involved. A new CAD file format, the Additive Manufacturing File (AMF) format, was introduced in 2011 to solve this problem.
[0118]Before printing a 3D model from an STL file, it must first be examining for errors. Most CAD application produce errors in output STL files of the following types: holes; face normal; self-intersections; noise shells; and manifold errors. A step in the STL generation known as “repair” fixes such problems in the original model. Generally, STLs that have been produced from a model obtained through 3D scanning often have more of these errors. This is due to how 3D scanning works. As it is often by point to point acquisition, 3D reconstruction will include errors in most cases.
[0119]Once completed, the STL file needs to be processed by a piece of software called a “slicer,” which converts the model into a series of thin layers and produces a G-code file containing instructions tailored to a specific type of 3D printer (FDM printers). This G-code file can then be printed with 3D printing client software (which loads the G-code, and uses it to instruct the 3D printer during the 3D printing process).
[0120]Printer resolution describes layer thickness and X-Y resolution in dots per inch (dpi) or micrometers (μm). Typical layer thickness is around 100 μm (250 DPI), although some machines can print layers as thin as 16 μm (1,600 DPI). X-Y resolution is comparable to that of laser printers. The particles (3D dots) are around 50 to 100 μm (510 to 250 DPI) in diameter. For that printer resolution, specifying a mesh resolution of 0.01-0.03 mm and a chord length ≤0.016 mm generate an optimal STL output file for a given model input file. Specifying higher resolution results in larger files without increase in print quality.
[0121]Though the printer-produced resolution is sufficient for many applications, greater accuracy can be achieved by printing a slightly oversized version of the desired object in standard resolution and then removing material using a higher-resolution subtractive process. The layered structure of all Additive Manufacturing processes leads inevitably to a strain-stepping effect on part surfaces which are curved or tilted in respect to the building platform. The effects strongly depend on the orientation of a part surface inside the building process. Some printable polymers such as ABS, allow the surface finish to be smoothed and improved using chemical vapor processes based on acetone or similar solvents. Some additive manufacturing techniques are capable of using multiple materials in the course of constructing parts. These techniques are able to print in multiple colors and color combinations simultaneously, and would not necessarily require painting. Some printing techniques require internal supports to be built for overhanging features during construction. These supports must be mechanically removed or dissolved upon completion of the print. All of the commercialized metal 3D printers involve cutting the metal component off the metal substrate after deposition. A new process for the GMAW 3D printing allows for substrate surface modifications to remove aluminum or steel.
[0122]A large number of additive processes are available. The main differences between processes are in the way layers are deposited to create parts and in the materials that are used. Some methods melt or soften the material to produce the layers, for example. selective laser melting (SLM) or direct metal laser sintering (DMLS), selective laser sintering (SLS), fused deposition modeling (FDM), or fused filament fabrication (FFF), while others cure liquid materials using different sophisticated technologies, such as stereolithography (SLA). With laminated object manufacturing (LOM), thin layers are cut to shape and joined together (e.g., paper, polymer, metal). Each method has its own advantages and drawbacks, which is why some companies offer a choice of powder and polymer for the material used to build the object. Others sometimes use standard, off-the-shelf business paper as the build material to produce a durable prototype. The main considerations in choosing a machine are generally speed, costs of the 3D printer, of the printed prototype, choice and cost of the materials, and color capabilities. Printers that work directly with metals are generally expensive. However less expensive printers can be used to make a mold, which is then used to make metal parts.
[0123]Fused deposition modeling (FDM), derives from automatic polymeric foil hot air welding system, hot-melt gluing and automatic gasket deposition. In fused deposition modeling, the model or part is produced by extruding small beads or streams of material which harden immediately to form layers. A filament of thermoplastic or other low melting point material or mixture is fed into an extrusion nozzle head (3D printer extruder), where the filament is heated to its melting temperature and extruded onto a build table. More recently, fused pellet deposition (or fused particle deposition) has been developed, where particles or pellets of plastic replace the need to use filament. The nozzle head heats the material and turns the flow on and off. Typically stepper motors or servo motors are employed to move the extrusion head and adjust the flow. The printer usually has 3 axes of motion. A computer-aided manufacturing (CAM) software package is used to generate the G-Code that is sent to a microcontroller which controls the motors.
[0124]Plastic is the most common material for such printing. Various polymers may be used, including acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polylactic acid (PLA), high-density polyethylene (HDPE), PC/ABS, polyphenylsulfone (PPSU) and high impact polystyrene (HIPS). In general, the polymer is in the form of a filament fabricated from virgin resins. There are multiple projects in the open-sourced community aimed at processing post-consumer plastic waste into filament. These involve machines used to shred and extrude the plastic material into filament such as recyclebots. Additionally, fluoropolymers such as PTFE tubing are used in the process due to the material's ability to withstand high temperatures. This ability is especially useful in transferring filaments.
[0125]FDM is somewhat restricted in the variation of shapes that may be fabricated. For example, FDM usually cannot produce stalactite-like structures, since they would be unsupported during the build. Otherwise, a thin support must be designed into the structure, which can be broken away during finishing. Usually, the software that converts the 3D model into a set of flat layers, called slicer, takes care of the addition of these supports and some other resources to allow the fabrication of this kind of shapes.
[0126]Another 3D printing approach is the selective fusing of materials in a granular bed. The technique fuses parts of the layer and then moves upward in the working area, adding another layer of granules and repeating the process until the piece has built up. This process uses the unfused media to support overhangs and thin walls in the part being produced, which reduces the need for temporary auxiliary supports for the piece. For example, in selective heat sintering, a thermal printhead applies heat to layers of powdered thermoplastic; when a layer is finished, the powder bed moves down, and an automated roller adds a new layer of material which is sintered to form the next cross-section of the model; using a less intense thermal printhead instead of a laser, makes this a cheaper solution than using lasers, and can be scaled down to desktop sizes.
[0127]Laser sintering techniques include selective laser sintering (SLS), with both metals and polymers (e.g., PA, PA-GF, Rigid GF, PEEK, PS, Alumide, Carbonmide, elastomers), and direct metal laser sintering (DMLS).
[0128]Selective laser melting (SLM) does not use sintering for the fusion of powder granules but will completely melt the powder using a high-energy laser to create fully dense materials in a layer-wise method that has mechanical properties similar to those of conventional manufactured metals.
[0129]Electron beam melting (EBM) is a similar type of additive manufacturing technology for metal parts (e.g. titanium alloys). EBM manufactures parts by melting metal powder layer by layer with an electron beam in a high vacuum. Unlike metal sintering techniques that operate below melting point, EBM parts are void-free.
[0130]The binder jetting 3D printing technique is the deposition of a binding adhesive agent onto layers of material, usually powdered. The materials can be ceramic-based or metal. This method is also known as inkjet 3D printing system. To produce the piece, the printer builds the model using a head that moves over the platform base and deposits, one layer at a time, by spreading a layer of powder (plaster, or resins) and printing a binder in the cross-section of the part using an inkjet-like process. This is repeated until every layer has been printed. This technology allows the printing of full color prototypes, overhangs, and elastomer parts. The strength of bonded powder prints can be enhanced with wax or thermoset polymer impregnation.
[0131]The Stereolithography (SLA) process is based on light curing (photopolymerization) of liquid materials into a solid shape. In this process a vat of liquid polymer is exposed to controlled lighting (like a laser or a digital light projector) under safelight conditions. Most commonly the exposed liquid polymer hardens through cross-linking driven by the addition reaction of carbon carbon double bonds in acrylates. Polymerization occurs when photopolymers are exposed to light when photopolymers contain chromophores, otherwise, the addition of molecules that are photosensitive are utilized to react with the solution to begin polymerization. Polymerization of monomers lead to cross-linking, which creates a polymer. Through these covalent bonds, the property of the solution is changed. The build plate then moves down in small increments and the liquid polymer is again exposed to light. The process repeats until the model has been built. The liquid polymer is then drained from the vat, leaving the solid model. The EnvisionTEC Perfactory is an example of a DLP rapid prototyping system.
[0132]Inkjet printer systems like the Objet PolyJet system spray photopolymer materials onto a build tray in ultra-thin layers (between 16 and 30 μm) until the part is completed. Each photopolymer layer is cured with UV light after it is jetted, producing fully cured models that can be handled and used immediately, without post-curing. The gel-like support material, which is designed to support complicated geometries, is removed by hand and water jetting. It is also suitable for elastomers. There is another type of inkjet printing system available in the market that can print a photopolymer in a layer-by-layer manner, with intermediate UV curing, to produce ophthalmic corrective lenses. No support structures are required in this case, as ophthalmic lenses do not need overhangs. Luxexcel, a Dutch company, has commercialized this technology and printing platform.
[0133]Ultra-small features can be made with the 3D micro-fabrication technique used in multiphoton photopolymerisation. This approach uses a focused laser to trace the desired 3D object into a block of gel. Due to the nonlinear nature of photo excitation, the gel is cured to a solid only in the places where the laser was focused while the remaining gel is then washed away. Feature sizes of under 100 nm are easily produced, as well as complex structures with moving and interlocked parts. Yet another approach uses a synthetic resin that is solidified using LEDs.
[0134]In Mask-image-projection-based stereolithography, a 3D digital model is sliced by a set of horizontal planes. Each slice is converted into a two-dimensional mask image. The mask image is then projected onto a photocurable liquid resin surface and light is projected onto the resin to cure it in the shape of the layer. The technique has been used to create objects composed of multiple materials that cure at different rates. In research systems, the light is projected from below, allowing the resin to be quickly spread into uniform thin layers, reducing production time from hours to minutes. Commercially available devices such as Objet Connex apply the resin via small nozzles.
[0135]Continuous liquid interface production (CLIP) is another form of additive manufacturing that uses the DLP based photo polymerization process to create smooth-sided solid objects of a wide variety of shapes. The continuous process of CLIP begins with a pool of liquid photopolymer resin. Part of the pool bottom is transparent to ultraviolet light (the “window”). Like DLP systems before it, ultraviolet light beam shines through the window, illuminating the precise cross-section of the object. The light causes the resin to solidify. The object rises slowly enough to allow resin to flow under and maintain contact with the bottom of the object.[37] CLIP is different from traditional DLP processes, due to an oxygen-permeable membrane which lies below the resin, creating a “dead zone” (persistent liquid interface) preventing the resin from attaching to the window (photopolymerization is inhibited between the window and the polymerizer).
[0136]Unlike stereolithography, the printing process is considered continuous by its founders and considerably faster than traditional DLP processes, enabling the production of parts in minutes instead of hours.
[0137]Recently, the use of stereolithographic 3D printing techniques has been developed further to allow for the additive manufacturing of ceramic materials. Successful 3D printing of ceramics using stereolithography is achieved through the photopolymerisation of preceramic polymers to yield silicon based ceramics of a class known more widely as polymer derived ceramics, including silicon carbide and silicon oxycarbide.
[0138]Computed axial lithography is a method for 3D printing based on reversing the principle of computed tomography (CT) to create prints in photo-curable resin. Unlike other methods of 3D printing it does not build models through depositing layers of material like fused deposition modelling and stereolithography, instead it creates objects using a series of 2D images projected onto a cylinder of resin. It is notable for its ability to build objects much more quickly than other methods using resins and the ability to embed objects within the prints.
[0139]Liquid additive manufacturing (LAM) is an additive manufacturing technique which deposits a liquid or highly viscous material (e.g Liquid Silicone Rubber) onto a build surface to create an object, which is then vulcanised using heat to harden it.
[0140]In powder-fed directed-energy deposition, a high-power laser is used to melt metal powder supplied to the focus of the laser beam. The laser beam typically travels through the center of the deposition head and is focused to a small spot by one or more lenses. The build occurs on a X-Y table which is driven by a tool path created from a digital model to fabricate an object layer by layer. The deposition head is moved up vertically as each layer is completed. Metal powder is delivered and distributed around the circumference of the head or can be split by an internal manifold and delivered through nozzles arranged in various configurations around the deposition head. A hermetically sealed chamber filled with inert gas or a local inert shroud gas is often used to shield the melt pool from atmospheric oxygen for better control of material properties. The powder fed directed energy process is similar to Selective Laser Sintering, but the metal powder is applied only where material is being added to the part at that moment. The process supports a wide range of materials including titanium, stainless steel, aluminum, and other specialty materials as well as composites and functionally graded material. The process can not only fully build new metal parts but can also add material to existing parts for example for coatings, repair, and hybrid manufacturing applications. LENS (Laser Engineered Net Shaping), which was developed by Sandia National Labs, is one example of the Powder Fed—Directed Energy Deposition process for 3D printing or restoring metal parts.
[0141]Laser-based wirefeed systems, such as Laser Metal Deposition-wire (LMD-w), feed wire through a nozzle that is melted by a laser using inert gas shielding in either an open environment (gas surrounding the laser), or in a sealed chamber. Electron beam freeform fabrication uses an electron beam heat source inside a vacuum chamber.
[0142]It is also possible to use conventional gas metal arc welding attached to a 3D stage to 3-D print metals such as steel and aluminum. Low-cost open source RepRap-style 3-D printers have been outfitted with Arduino-based sensors and demonstrated reasonable metallurgical properties from conventional welding wire as feedstock.
Continuous Digital Light Processing
[0143]cDLP is a type of the standardized additive manufacturing process called Vat photopolymerization, in which, liquid photopolymer in a vat is selectively cured by light-activated polymerization (ASTM-F2792). Synonyms as “constrained-surface stereolithography”, “projection stereolithography”, “bottom-up mask-projection stereolithography”, “digital light processing stereolithography”, “digital micromirror device-based printing”, etc. have been used to describe cDLP. cDLP has great potential in the fabrication of high accuracy porous scaffolds for BTE in the micrometrical scale. cDLP employs ultraviolet light by projecting it to the resin activating initiators that crosslink the polymer layer, using dynamic masks to cure a whole layer at a time sequentially. Hence, this technique offers a significantly higher building speed than standard stereolithography (Dean et al. 2012).
[0144]A typical stereolithography system builds parts top down using a simple point laser. In cDLP, the vat is illuminated vertically upwards through a transparent window or “basement”. After the system irradiates a binary layer, the cured resin sticks to the window and cures with the previous layer. The “build” platform pulls away from the window vertically or at a slight tilting angle to smoothly separate the part from the window. Three advantages of this system are remarkable. First, no separate recoating mechanism is needed since gravity forces refill the resin in the vat (i.e., region between the cured part and over the window). Second, the top vat surface being irradiated is a flat window, not a free surface, enabling more precise layers to be fabricated. Third, some cDLP systems have a build process that eliminates a regular vat as they have a supply-on-demand material feed system instead. The main disadvantage is that small or fine features may be damaged when the cured layer is separated from the window (Gibson, Rosen, and Stucker 2015).
[0145]A continuous digital light processing (cDLP) device includes a digital micro-mirror device (DMD) projector. A DMD consists of an array of micro-mirrors which controls the intensity of projected light in each pixel of the layer image, effectively polymerizing each voxel (volumetric pixel) of each layer of the implant IMP. The term “continuous” in continuous digital light processing indicates that all voxels within a layer can be projected simultaneously, as opposed to the successive drawing (i.e., moving of laser beam) of voxels that occurs in other additive manufacturing methods such as stereolithography. cDLP based additive manufacturing projects multiple voxels that may add up to a complete implant layer as one image, or “voxel mask.” This allows for the entire layer to be cured simultaneously (i.e., continuous curing).
[0146]The projector projects light through a transparent or translucent basement plate above which is a resin including a liquid light-polymerizable material. Exposure to the light causes the resin to at least partially cure or polymerize to form layers of the implant IMP. In some embodiments, the device further includes a build plate to which the implant IMP operatively attaches. The build plate may operatively attach to a motor, the operation of which successively shifts or elevates the build plate away from the basement plate as the light successively cures or polymerizes the resin to form each layer of the implant IMP. The light further polymerizes or overcures previously rendered layers to bind or stitch newly polymerized layers to the previous layers.
[0147]In one embodiment, the cDLP device is the Perfactory® UV device produced by envisionTEC (Gladbeck, Germany). In another embodiment, the cDLP device would be a cDLP device other than the Perfactory® UV device produced by envisionTEC.
[0148]In one embodiment, each projected voxel mask also uses spatially varying irradiance, meaning that each pixel may be assigned a different light intensity value. Benefits of assigning each pixel a different intensity value include the ability of varying curing rates within a layer and allowing for anti-aliasing methods analogous to those found in image processing. In one embodiment, the cDLP device is equipped with an Enhanced Resolution Module (ERM) (not shown) which effectively doubles the within-layer (x-y) resolution through a process similar to pixel shifting, a technique which increases the true resolution of devices by moving the micro-mirrors by fractions of a pixel in the x and y directions.
[0149]The unique properties of cDLP rendering allow for improved accuracy defined as the similarity of the resulting implant or scaffold to the shape found in the design, or CAD, file. One source of increased accuracy is in-plane (x-y) resolution, which is a function of the projector lens magnification and the resolution of the DLP chip. Pixel sizes may be 75 micrometers or less. ERM, pixel shifting, anti-aliasing, or combinations thereof may further increase the in-plane resolution by at least a factor of 2.
[0150]The cDLP device further provides increased accuracy due to increased between-plane or (z) resolution. The between-plane (z) resolution is controlled by, among other factors, the motor (not shown), which shifts the build plate between serial layers. In one embodiment, the device has a motor capable of increments of 50 micrometers and as small as 15 micrometers. The between-plane (z) resolution may be further controlled by controlling the depth of penetration of the light to limit polymerizing energy into the resin or previously rendered layers of the implant IMP.
[0151]A model of the Perfactory® UV device has a motor capable of increments of 50 micrometers and a 60 millimeter lens, providing an in-plane (x-y) native resolution of 71 micrometers and 35.5 micrometers utilizing pixel shifting. Thus this model of the Perfactory® UV device is capable of continuously polymerizing 35.5×35.5×50 urn voxels. Another model of the Perfactory® UV device would have a 75 millimeter lens that would provide a 42 micrometer native in-plane (x-y) resolution and 21 micrometers resolution with pixel shifting.
Light-Polymerizable Materials
[0152]The cDLP process controls mechanical and other properties of the resulting implant IMP, in part, by controlling the molecular weight of the light-polymerizable material. Manipulation of the material's molecular weight adjusts the strength of the resulting implant IMP, with higher molecular weights generally being stronger. Thus, for applications where the implant IMP would bear significant mechanical stress, the light-polymerizable material may be chosen such that the rendered part may adequately handle and transmit the mechanical stress.
[0153]In applications such as implants or scaffolds, which are intended for implantation in a patient's body, it is important that components of the implant or scaffold including the light-polymerizable material as well as any initiators, dyes, solvents, and other substances be biocompatible, meaning that the implant poses no substantial risk of injury or toxicity to living cells, tissues, or organs, and poses no substantial risk of rejection by the immune system. In some instances, it is possible to use some non-biocompatible components or processes. However, they would usually be fully removed or rendered biocompatible prior to implantation. For example, some non-biocompatible chemicals may be used during the manufacturing process but be fully removed before implantation.
[0154]In applications such as tissue engineering scaffolds, resorbability of the scaffold, the ability of the part to break down in the host's body, is a very important consideration. It is important to the regeneration of tissue such as bone that the scaffold resorb in response to cell maturation and incoming host tissue. Well-timed scaffold resorption is important for successful integration of vasculature to allow unfettered remodeling and host incorporation of neotissue. Thus, predictable scaffold resorption is important including predictable rates of loss of material properties, predictable rates of scaffold degradation (e.g., it may be useful to choose polymers that fracture or erode at predictable rates rather than bulk degrade), and predictable rates pH change.
[0155]Strength and stiffness of the scaffold must be weighed against rates of resorbability of the scaffold. Manipulation of the material's molecular weight generally adjusts resorption levels versus strength of the scaffold with higher molecular weights resulting in stronger but less resorbable scaffolds and lower molecular weights resulting in weaker but more resorbable scaffolds.
[0156]Low molecular weight polymers are often capable of safely breaking down and be resorbed within the body. In general, resorbable polymers are often of very low molecular weight compared to polymers used in common automotive, aerospace, and industrial applications. Resorbable polymers usually have as low as 2-3 orders of magnitude lower molecular weight than the polymers used in those applications.
[0157]Low molecular weight polymers are often capable of safely breaking down and be resorbed within the body. In general, resorbable polymers are often of very low molecular weight compared to polymers used in common automotive, aerospace, and industrial applications. Resorbable polymers usually have as low as 2-3 orders of magnitude lower molecular weight than the polymers used in those applications.
[0158]In one embodiment, the cDLP process of the present disclosure uses the resorbable polymer poly(propylene fumarate) or PPF as the light-polymerizable material. PPF incorporates most of the characteristics discussed above for the light-polymerizable material including low molecular weight, no toxicity and resorbability. In another embodiment, the cDLP process of the present disclosure uses a resorbable light-polymerizable material other than PPF. In yet another embodiment, the cDLP process of the present disclosure uses a light-polymerizable material that although not resorbable is biocompatible or bioneutral. In one embodiment, the liquid light-polymerizabl