Drug-eluting surgical articles and methods of using the same

Abstract

This specification discloses a biological material for treating a condition and methods of using the same. The biological material of the present disclosure can be, for example, a surgical article. By implanting the biological material disclosed herein into a subject, for example, cancer can be treated. In the biological material, a first geometric element of a first plurality of geometric elements and a first plurality of geometric elements including a therapeutically effective amount of a therapeutic agent are formed by a first porous boundary, and the first porous boundary includes a polymer and a therapeutic agent and includes a first plurality of geometric elements and a therapeutically effective amount of a therapeutic agent. A first geometric element of the first plurality of geometric elements is formed by a first porous boundary, and the first porous boundary can include a polymer and a therapeutic agent.

Description

Technical Field

[0001] Cross-reference This application claims priority and benefit under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 342,012, filed May 13, 2022, and U.S. Provisional Patent Application No. 63 / 342,531, filed May 16, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] Description of Federally Sponsored Research This invention was made with government support under Grant No. 7203584328 awarded by the National Science Foundation. The United States government has certain rights in this invention.

Background Art

[0003] Background Transplantation of biomaterials can enable the targeted delivery of a therapeutically effective amount of a therapeutic agent. Targeted delivery of a therapeutic agent can increase the effectiveness of the agent by increasing the exposure of the target tissue to the agent and reducing systemic toxicity.

[0004] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Summary of the Invention

Means for Solving the Problems

[0005] Abstract In some embodiments, the present disclosure provides a biomaterial comprising a first plurality of geometric elements and a therapeutically effective amount of a therapeutic agent, wherein a first geometric element of the first plurality of geometric elements is formed by a first porous boundary, the first porous boundary comprising a polymer and the therapeutic agent, a second geometric element of the first plurality of geometric elements is formed by a first solid region comprising a non-porous boundary and a polymer, the therapeutic agent cannot diffuse into the second geometric element, the first solid region is adjacent to and present within the non-porous boundary, and a portion of the first porous boundary is adjacent to a portion of the non-porous boundary.

[0006] In some embodiments, the present disclosure provides a method of treating a condition, the method comprising implanting a biomaterial into a subject, the biomaterial comprising a first plurality of geometric elements and a therapeutically effective amount of a therapeutic agent, wherein a first geometric element of the plurality of geometric elements is formed by a first porous boundary, the first porous boundary comprising a polymer and the therapeutic agent, a second geometric element of the first plurality of geometric elements is formed by a first solid region comprising a non-porous boundary and a polymer, the therapeutic agent cannot diffuse from the first porous boundary into the second geometric element, the first solid region is adjacent to and present within the non-porous boundary, and a portion of the first porous boundary is adjacent to a portion of the non-porous boundary.

[0007] In some embodiments, the present disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a biomaterial comprising a plurality of geometric elements and a therapeutic agent, wherein (a) a first geometric element of the plurality of geometric elements comprises a first polymer and the therapeutic agent, and at least a portion of the first geometric element is porous; (b) a second geometric element of the plurality of geometric elements comprises a second polymer, and at least a portion of the second geometric element is substantially non-porous; (c) at least a portion of the first geometric element is adjacent to at least a portion of the second geometric element; and (d) the first polymer or the second polymer has a number average molar mass greater than 6,000 Daltons (Da).

[0008] In some embodiments, the present disclosure provides a method of treating a condition of a subject in need thereof, the method comprising administering to the subject a biomaterial comprising a plurality of geometric elements and a therapeutic agent, wherein (a) a first geometric element of the plurality of geometric elements comprises a first polymer and a therapeutic agent, the amount of the therapeutic agent in the first geometric element being greater than 30% relative to the weight of the first polymer, and at least a portion of the first geometric element being porous; (b) a second geometric element of the plurality of geometric elements is formed by a second polymer, and at least a portion of the second geometric element being substantially non-porous; and (c) at least a portion of the first geometric element is adjacent to at least a portion of the second geometric element. BRIEF DESCRIPTION OF THE DRAWINGS

[0009]

Figure 1A

[0010]

Figure 1B

[0011]

Figure 2

[0012]

Figure 3

[0013]

Figure 4A

[0014]

Figure 4B

[0015]

Figure 5

[0016]

Figure 6

[0017]

Figure 7

[0018]

Figure 8

[0019]

Figure 9

[0020]

Figure 10

[0021]

Figure 11

[0022]

Figure 12

[0023]

Figure 13

[0024]

Figure 14

[0025]

Figure 15

[0026]

Figure 16

[0027]

Figure 17

Mode for Carrying Out the Invention

[0028] Detailed Description Target delivery systems for therapeutic agents can increase the effectiveness of therapeutic agents, for example, by increasing the exposure of target tissues to the therapeutic agent and by reducing systemic toxicity. Target delivery may be desirable in the case of highly toxic treatments, such as chemotherapy agents and opioids, when administered systemically and / or over a long period of time.

[0029] Advances in three - dimensional (3D) printing technology can create new opportunities for manufacturing customized delivery systems that can be adapted for widespread use in the operating room. Three - dimensional printing can be advantageous due to the relatively low cost, simplicity, and versatility of 3D printing systems, as well as the ability to manufacture custom devices at high speed.

[0030] This specification discloses a surgical article and / or a biomaterial that can function as a drug delivery system capable of directly releasing a therapeutic agent to a target site over a long period of time. The biomaterial can include one or more therapeutic agents filled in one or more geometric elements of the article. The biomaterial, such as a surgical article, can be adapted to sustainably release one or more therapeutic agents in situ. In some embodiments, the surgical article is printed using an extrusion 3D printing method. The biomaterial can be custom printed in a shape and size suitable for covering the in situ target site. The biomaterial for in situ implantation can be in the general form of a surgical tape or mesh that can also be folded and / or laminated. Suitable target sites include any site within the body of a subject in need of treatment with one or more therapeutic agents. Non-limiting examples of target sites include tissues such as blood vessels, lymph nodes, cartilage, bone, liver, lung, heart, pancreas, spleen, gastrointestinal tract, brain, pelvis, breast, and lung tissue. In some embodiments, the biomaterial can be applied to deep tissues and connective tissues, such as muscle and smooth muscle.

[0031] The biomaterials disclosed herein can include a polymeric material capable of dispersing one or more therapeutic agents in at least a portion thereof. In some embodiments, the polymeric material can also contain one or more additives. The polymeric material can include or consist of one or more bioresorbable and / or biodegradable polymers, or a mixture of polymers including at least one bioresorbable and / or biodegradable polymer.

[0032] In some implementation forms, the 3D printed surgical article is sterile, sterilizable, and / or sterilized before being implanted into a subject.

[0033] The biomaterials disclosed herein can be biocompatible. Biocompatible biomaterials can be administered or implanted into a subject's body without undesirable effects such as, for example, immune and / or inflammatory responses.

[0034] The biomaterials disclosed herein can be biodegradable. Biodegradable biomaterials can be metabolized in the body or broken down (partially or completely) into non-toxic products that can be excreted from the body under physiological conditions. In some cases, biodegradable materials are broken down by enzymatic activity, such as by enzymatic hydrolysis.

[0035] In some embodiments, the biomaterials of the present disclosure are bioresorbable or biodegradable. Bioresorbable or biodegradable materials can be broken down and absorbed by cells and / or tissues.

[0036] In some embodiments, the biomaterials described herein are configured to be resorbed and / or degraded over a period ranging from about 1 day to about 1 week, about 1 week to about 1 month, 1 month to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, about 12 months to about 24 months, or about 2 years to about 5 years after being placed in situ. The time of resorption and / or degradation can be adjusted by controlling the composition of the polymeric material, including the type of polymer and the porosity of the material, as well as by the two-dimensional and three-dimensional arrangement of the geometric elements that make up the article.

[0037] The surgical articles described herein can include one geometric element or a plurality of geometric elements. In some embodiments, some of the plurality of geometric elements are in fluid communication with each other. In some embodiments, the plurality of geometric elements are printed on the x-y plane as, for example, ribbons, grids, or other shapes to form a biomaterial of a desired shape and / or size. In some embodiments, the plurality of geometric elements can be printed perpendicular to each other. In some embodiments, the thickness of the single-layer article can range from about 0.1 cm to about 1 cm, about 0.25 to about 1 cm, about 0.5 to about 1 cm, about 0.75 to about 1 cm, about 0.1 cm to about 2 cm, about 0.25 to about 2 cm, about 0.5 to about 2 cm, about 0.75 to about 2 cm, about 0.1 cm to about 3 cm, about 0.25 to about 3 cm, about 0.5 to about 3 cm, about 0.75 to about 3 cm, about 0.1 cm to about 4 cm, about 0.25 to about 4 cm, about 0.5 to about 4 cm, about 0.75 to about 4 cm, about 0.1 cm to about 5 cm, about 0.25 to about 5 cm, about 0.5 to about 5 cm, or about 0.75 to about 5 cm.

[0038] In some embodiments, the biomaterials of the present disclosure include multiple layers, and each layer includes a plurality of geometric elements. For example, the biomaterials of the present disclosure can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 layers, or more. In some embodiments, each layer of the biomaterial is oriented such that the layer is offset from the upper and / or lower units at a defined angle, for example, at an angle such as about 15 degrees, about 30 degrees, about 45 degrees, about 60 degrees, about 90 degrees, about 105 degrees, about 120 degrees, about 135 degrees, about 150 degrees, about 165 degrees, or about 180 degrees.

[0039] The overall dimensions of the biomaterials of the present disclosure can be adapted to fit a wide range of in-situ target sites. According to any of these implementations, one or more of the plurality of geometric elements can be printed with or without one or more therapeutic agents. The biomaterials of the present disclosure can have any shape. For example, the overall shape of the surgical article according to this description can be circular, oval, rectangular, triangular, octagonal, pentagonal, hexagonal, heptagonal, or square, and the size can be, for example, about 4 cm 2 ~ about 200 cm 2 and can be adapted to cover an area in the range. In some embodiments, the article is about 20 cm 2 ~ about 50 cm 2 , about 50 cm 2 ~ about 100 cm 2 , or about 100 cm 2 ~ about 200 cm 2 and is sized to be suitable for covering the area. In some embodiments, the article can be sized in the range from about 2 cm × about 2 cm to about 12 cm × about 10 cm. For example, the biomaterials of the present disclosure can be square articles of 2 cm × 2 cm, 4 cm × 4 cm, 6 cm × 6 cm, or 8 cm × 8 cm, or rectangular articles of 4 cm × 6 cm, 8 cm × 6 cm, 10 cm × 8 cm, or 12 cm × 10 cm.

[0040] In some embodiments, the biomaterials of the present disclosure (e.g., surgical articles) can further include loops or similar features configured to facilitate placement of the biomaterials in-situ, for example, by suturing.

[0041] The biomaterials disclosed herein can have a flexible structure. The biomaterials can be dosage forms that are administered locally using minimally invasive / endoscopic procedures. The biomaterials can enable 5-FU to directly target tumor cells at tumor sites that are difficult to reach. This site-specific delivery technology has the potential to reduce side effects caused by systemic therapy. The biomaterials can shrink local tumors, relieve local symptoms, and potentially prevent or reduce the possibility of life-changing surgeries such as colostomy.

[0042] In some embodiments, the biomaterials disclosed herein are radiopaque. In some embodiments, the biomaterials disclosed herein do not contain, or substantially do not contain, additives or fillers other than the drugs and excipients (e.g., PCL) disclosed herein. In some embodiments, the biomaterials release the active pharmaceutical ingredient (API) in a sustained release (e.g., biphasic release) manner from pores within the biodegradable polymer over a period of four weeks. The release can be enhanced by the hydrophobicity of the product polymer. Structure of geometric elements.

[0043] The biomaterials of the present disclosure can include a plurality of geometric elements. Some of the geometric elements among the plurality of geometric elements can be adjacent to each other and / or in fluid communication. In some embodiments, the geometric elements form a layer. The geometric elements can be formed by a boundary including a polymer. In some embodiments, the boundary of the geometric elements can further include one or more therapeutic agents disclosed herein. The boundary forming the geometric elements can be porous, non-porous, or minimally porous. The porous boundary can enable the therapeutic agent to diffuse through the boundary and into or out of the geometric elements formed by the boundary. In some embodiments, the boundary is minimally porous, and thus the therapeutic agent cannot diffuse through the boundary into the geometric elements formed by the boundary.

[0044] The geometric elements formed by the boundary can, for example, include an empty space or a solid region within the boundary. The solid region of the geometric element can be porous, non-porous, or minimally porous. The porous solid region can enable a therapeutic agent to diffuse through the solid boundary and into or out of the geometric element. In some embodiments, the solid region is minimally porous, and thus the therapeutic agent cannot diffuse through the solid region and into the geometric element formed by the boundary.

[0045] The boundaries and / or solid regions of the geometric elements can have porosity. In some embodiments, the porosity of the boundary or solid region is from about 10% to about 99%. In some embodiments, the porosity of the boundary or solid region is from about 10% to about 20%, from about 10% to about 30%, from about 10% to about 40%, from about 10% to about 50%, from about 10% to about 60%, from about 10% to about 70%, from about 10% to about 80%, from about 10% to about 90%, from about 10% to about 99%, from about 20% to about 30%, from about 20% to about 40%, from about 20% to about 50%, from about 20% to about 60%, from about 20% to about 70%, from about 20% to about 80%, from about 20% to about 90%, from about 20% to about 99%, from about 30% to about 40%, from about 30% to about 50%, from about 30% to about 60%, from about 30% to about 70%, from about 30% to about 80%, from about 30% to about 90%, from about 30% to about 99%, from about 40% to about 50%, from about 40% to about 60%, from about 40% to about 70%, from about 40% to about 80%, from about 40% to about 90%, from about 40% to about 99%, from about 50% to about 60%, from about 50% to about 70%, from about 50% to about 80%, from about 50% to about 90%, from about 50% to about 99%, from about 60% to about 70%, from about 60% to about 80%, from about 60% to about 90%, from about 60% to about 99%, from about 70% to about 80%, from about 70% to about 90%, from about 70% to about 99%, from about 80% to about 90%, from about 80% to about 99%, or from about 90% to about 99%. In some embodiments, the porosity of the boundary or solid region is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99%. In some embodiments, the porosity of the boundary or solid region is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the porosity of the boundary or solid region is at most about 20%, at most about 30%, at most about 40%, at most about 50%, at most about 60%, at most about 70%, at most about 80%, at most about 90%, or at most about 99%.

[0046] The porosity of the boundary and / or solid region can vary throughout the biomaterials of the present disclosure. In some embodiments, a porous boundary surrounds a minimally porous or non-porous solid region. In some embodiments, a minimally porous or non-porous boundary surrounds a porous solid region. In some embodiments, a non-porous or minimally porous boundary surrounds a non-porous or minimally porous solid region. In some embodiments, a porous boundary surrounds a porous solid region.

[0047] Adjacent geometric elements share an end and can thus form part of the boundary that forms the geometric element. In some embodiments, adjacent elements each include different ends / boundaries that are adjacent to and / or in contact with each other.

[0048] The boundary can form geometric elements of any shape. For example, the boundary can form geometric elements that are circular, elliptical, triangular, rectangular, pentagonal, hexagonal, heptagonal, octagonal, or irregular in shape. In some embodiments, the boundary forms a nonagonal or decagonal geometric element. Some of the geometric elements among the plurality of geometric elements can be of the same or different shapes. In some embodiments, the biomaterial or layer thereof can include two or more hexagonal, triangular, and rhombic shapes, or a plurality of geometric elements that define a part thereof. In some implementation forms, the length of the end of a particular element can be in the range of 1.0 mm to 10 mm, or 1.0 mm to 5 mm, or 1.0 mm to 3 mm. It is understood that depending on the geometric shape defined by the end of the element, the ends can be of the same or different lengths. In some embodiments, each end of the geometric element has a uniform length and / or width.

[0049] In some embodiments, the biomaterials disclosed herein are composed of multiple layers, and each layer is formed from a plurality of open geometric elements and filled geometric elements that form a defined pattern. The plurality of geometric elements can include elements having three, four, five, or six ends. In some embodiments, the ends of the elements can define one or more geometric shapes selected from triangles, rhombuses, hexagons, and portions of any of the foregoing. In some embodiments, the triangle is an equilateral triangle, and the ends of each geometric element are of uniform length. In some embodiments, the ends have a length of about 1 to about 3 mm, about 1 to about 2 mm, such as about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, or about 3.0 mm.

[0050] One or more therapeutic agents can be filled into the geometric elements. For example, one or more geometric agents can be dispersed within the solid regions or boundaries of one or more geometric elements of the biomaterials of the present disclosure. Arrangement of geometric elements.

[0051] In some embodiments, the plurality of geometric elements that form the biomaterial or layer thereof herein are arranged in a defined pattern of elements that includes solid regions (i.e., filled elements) and empty spaces (i.e., open elements), and this pattern is adapted to regulate in situ the release of therapeutic agent(s) from the drug storage element(s) of the unit article. For example, to regulate the release of one or more therapeutic agents from the article, the size and shape of the elements that form the biomaterial or layer thereof can be increased or reduced to regulate the surface area of the filled elements and the pore size of the open elements. The volume and number of the element(s) filled with the therapeutic agent(s) can determine the amount of therapeutic agent(s) in the unit article and the amount released in situ at the target site. The volume of the element(s) filled with the therapeutic agent(s) can be increased, for example, by printing multiple monolayers of the biomaterial on top of each other until a desired thickness is reached, thereby increasing the filled volume of the therapeutic agent(s). The defined pattern of open and filled geometric elements can be further used to regulate the total surface area of the unit article and the surface area of the unit article from which the therapeutic agent(s) is / are released. Release of therapeutic agent.

[0052] Release of one or more therapeutic agents from the biomaterials of the present disclosure to an in situ target site can occur from the exposed surface(s) of the biomaterial. Additionally or alternatively, one or more therapeutic agents can diffuse within the biomaterials disclosed herein.

[0053] For example, in some embodiments, a defined pattern of open and filled geometric elements having porous and / or non-porous components (e.g., boundaries or solid regions) is used to direct or concentrate the in vivo diffusion of any therapeutic agent into a defined region of the biomaterial. Concentrating the diffusion of the therapeutic agent can have the effect of releasing a more concentrated therapeutic agent from the region of the biomaterial. Thus, depending on the type of treatment, treatment duration, and location of the in situ target site, the amount and rate of release of the therapeutic agent(s) from the biomaterials described herein can be controlled by the defined pattern of open and filled geometric elements forming the biomaterial, the inclusion of one or more additives, such as poragen, and the amount of agent(s) filled into the geometric elements of the biomaterial.

[0054] In some embodiments, the release of the therapeutic agent from the biomaterials disclosed herein can be adjusted by increasing the thickness of the biomaterial (e.g., by using multiple layers) and by isolating the geometric element(s) filled with the therapeutic agent within the folded biomaterial or within the inner layer of the stack or layers of the biomaterial. By folding or stacking the biomaterial or its layers in this manner, the surface area from which the therapeutic agent is released can be reduced. In some embodiments, the surgical article can be formed from alternating layers of unit articles in a stacked configuration, where the alternating layers are offset or inclined, for example, by about 180 degrees, about 90 degrees, or about 45 degrees. For example, in an offset configuration, two or more layers of the biomaterial are horizontally laminated to each other at an angle of 180 degrees, 90 degrees, or 45 degrees. In some embodiments, the thickness of the folded or stacked article can range from about 0.5 cm to about 3 cm. In some embodiments, the thickness of the folded or stacked article is about 0.5 cm, about 1.0 cm, about 1.5 cm, or about 2.0 cm.

[0055] In some embodiments, in addition to, or instead of, dispersing one or more therapeutic agents within the polymeric material of the biomaterial, the surface of the biomaterial can be coated. Structure of the biomaterial.

[0056] A schematic diagram of a non-limiting example of the biomaterial of the present disclosure is shown in FIG. 1A. As shown in FIG. 1A, the biomaterial (100) of the present disclosure can include five different geometric shapes and 27 open (i.e., filled with empty space) or filled elements that define parts thereof. Two filled triangular elements (101) and seven filled rhombus-shaped elements (102) can be arranged to regulate the diffusion of a therapeutic agent injected within a portion of the biomaterial that includes adjacent filled hexagonal elements (103). In some embodiments, the filled elements each contain the same polymer or mixture of polymers. The filled elements can contain polymers or mixtures of polymers having the same or different porosities. For example, some of the filled elements can function as a barrier to the in-material diffusion of the therapeutic agent, while other filled elements can contain pores that serve to allow in-material diffusion of the therapeutic agent into regions defined by the filled porous elements. The porosity of the polymer constituting the biomaterial can be adjusted by the manufacturing process.

[0057] In FIG. 1A, the filled triangular element (101) is formed by a non-porous boundary (109) around an essentially non-porous solid region. The filled triangular element (109) can serve to concentrate the in-material diffusion of the therapeutic agent into adjacent regions defined by porous or open elements, such as filled hexagonal elements (103), open hexagonal elements (105), and / or open triangular elements and parts thereof (104). By concentrating the in-material diffusion, the release of the therapeutic agent can be targeted to defined regions of the biomaterial, for example, to release in a more concentrated manner in specific regions within an in-situ target site.

[0058] As shown in FIG. 1A, the biomaterial disclosed herein can include four filled hexagonal elements (103) formed by a porous boundary (108) and a solid region, each element including a polymer and a therapeutic agent dispersed within the polymer. The biomaterial can further include two filled rhombus-shaped elements (106) formed by the solid region and the porous boundary, each element including a polymer and a therapeutic agent dispersed within the polymer. In some embodiments, the porous boundary is formed by an end of the solid region. Across the biomaterial, the boundary between the geometric element and the solid region can have the same or a different composition than the composition of the solid region. In some embodiments, the biomaterial includes a porous boundary and a porous solid region in which no therapeutic agent is injected but which allows the therapeutic agent to diffuse into the rhombus-shaped filled elements (102) within the material, containing rhombus-shaped filled elements (102). When the therapeutic agent diffuses into the non-injected rhombus-shaped elements (102), the surface area through which the therapeutic agent diffuses to the in-situ target site increases.

[0059] The biomaterial disclosed herein can further include a plurality of filled and open elements that increase the overall surface area of the biomaterial, impart structural integrity to the biomaterial, impart flexibility to the biomaterial, and / or act as optional fixation points on the biomaterial. For example, as shown in FIG. 1A, the open elements (104, 105) of the biomaterial disclosed herein can act as fixation points for suturing the biomaterial in place at the target site. The boundary (107) forming the open elements (104, 105) can be a porous or non-porous boundary. In some embodiments, the boundary forming the open elements (104, 105) of the biomaterial disclosed herein includes a polymer and a therapeutic agent (e.g., 5-fluorouracil) injected within the polymer.

[0060] The biomaterials disclosed herein can be single-layer or multi-layer. For example, the biomaterials of the present disclosure can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 layers, or more. Non-limiting examples of single-layer biomaterials are shown in FIGS. 2A and 2B. FIG. 2A shows a front view, while FIG. 2B shows a rotational view of a single-layer article. Non-limiting examples of multi-layer biomaterials are shown in FIG. 3. FIG. 3 illustrates a laminated biomaterial containing three layers of the biomaterial described in FIG. 1, with each layer offset by approximately 30 degrees. Diffusion within the material.

[0061] In some embodiments, the biomaterials disclosed herein regulate the diffusion of therapeutic agents into and out of the biomaterial. Non-limiting examples of the pattern of diffusion of a therapeutic agent through the biomaterial (the biomaterial illustrated in FIG. 1A) disclosed herein are shown in FIG. 1B. In FIGS. 1A and 1B, the filled hexagonal elements (103) and rhombic elements (b) contain most of the therapeutic agent per unit of the biomaterial, but the ends defining the elements also contain the therapeutic agent. In some embodiments, the six filled hexagonal elements can contain a total of 50 - 500 mg, 100 - 400 mg, or 150 - 250 mg of the therapeutic agent. Each element can contain the same amount or different amounts of the therapeutic agent. In some embodiments, the therapeutic agent diffuses into the region defined by the filled rhombic-shaped elements (102), and the filled rhombic elements have a porosity that facilitates such diffusion. In some embodiments, the biomaterials disclosed herein further include filled rhombic elements (106) injected with the therapeutic agent that act as additional reservoirs for the therapeutic agent. Polymer.

[0062] The biomaterials described herein can be formed from 3D printed polymeric materials. In some embodiments, the polymeric material can include a bioresorbable and / or biodegradable polymer, or a mixture of polymers including one or more bioresorbable and / or biodegradable polymers. Suitable polymers include, but are not limited to, polycaprolactone (PCL), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (also interchangeably referred to as poly(lactide-co-glycolide) (PLGA)), poly(ethylene glycol) diacrylate (PEGDA), and poly(ester amide) copolymer (PEA).

[0063] In some embodiments, the polymeric material comprises or consists of PCL. In some embodiments, the polymeric material is a blend of PCL and one or more additional polymers. In some embodiments, the one or more additional polymers blended with PCL are selected from PLA, PLGA, and PEGDA. In some embodiments, the one or more additional polymers mixed with PCL are selected from polyvinyl chloride and polyethylene oxide (PEO), or PEA, polyester, poly(alpha-hydroxy acid), polylactone, polyorthoester, polycarbonate, polyanhydride, polyphosphazene, or gelatin-based polymers such as poly(ethylene glycol) (PEG)-gelatin methacrylate.

[0064] In some embodiments, the polymeric material is a blend of PCL and PLGA, such as a blend of PCL:PLGA of 1:1 to 10:1. In some embodiments, the polymeric material includes a mixture of PCL / PLGA of 1:1 to 5:1, a mixture of PCL / PLGA of 1:1 to 2:1. The lactide:glycolide ratio of PLGA can also be varied to adjust the release of the therapeutic agent and the degradation time in situ of the article. The percentage of PCL in the blend can determine the density of the copolymer, and the ratio of PCL to PLGA can indicate the number of elongated (extended) polymer fibers present in the copolymer. An increase in the number of elongated fibers throughout the polymeric article can increase the amount of drug released from the article. In some embodiments, the weight percentage of PLGA is lactide / glycolide of 50:50 to 90:10. In some embodiments, the weight percentage of PLGA is lactide / glycolide of 85:15, 60:40.

[0065] By adjusting the density and / or porosity of the polymeric material, the release of the therapeutic agent from the biomaterial can be regulated. For example, the release of the therapeutic agent can be increased by increasing the pore size of the polymeric material and / or increasing the porosity. In some embodiments, the polymeric material has a size in the range of 50 to 250 microns and includes or consists of PCL having micropores with an average size of about 80 microns. By blending PCL with another polymer, such as PLA, PLGA, PEGDA, or PEO, larger pores in the range of, for example, 200 to 800 microns can be obtained. In some embodiments, a polymeric material with lower porosity can be used to slow down the release of the therapeutic agent. For example, a polymeric material containing about 60% to 100% of PCL, or 60 to 80% of PCL, or 80 to 100% of PCL can be used.

[0066] In some embodiments, the biomaterials of the present disclosure can include geometric elements each containing two or more different polymer materials. For example, the polymer material forming the ends of the element may be different from the polymer material forming the "filling" of the filled element, and different filled elements may be filled with different polymer materials. The polymer materials may, for example, differ in the type of polymer or polymer mixture that makes up the polymer material. Additionally, the polymer materials forming different portions of the geometric element may have different densities and / or porosities, and may also differ in the additives they contain as required. For example, in a multi-head 3D printer, different substances can be printed simultaneously. For example, since each head can contain different components, one head can contain a selected polymer and a therapeutic agent, and a second head can contain only the polymer. When the STL file is converted to G-code, a programmable code for the multi-head printer is created, and the 3D printer can read which article segments contain PCL and which article segments contain PCL and a drug (as programmed). Similarly, two or more drugs can be printed at once. For example, an analgesic (e.g., an NSAID) can be printed simultaneously with a chemotherapeutic drug (e.g., 5-fluorouracil).

[0067] In some embodiments, the biomaterial includes a polymer (e.g., the first polymer and / or the second polymer disclosed herein), and the polymer has a number average molar mass of at least 0.5 kilodaltons (kDa), at least 1 kDa, at least 2 kDa, at least 5 kDa, at least 7 kDa, at least 10 kDa, at least 20 kDa, at least 30 kDa, at least 40 kDa, at least 50 kDa, at least 70 kDa, at least 100 kDa, at least 200 kDa, at least 500 kDa, at least 700 kDa, or at least 1,000 kDa.

[0068] In some embodiments, the biomaterial comprises a polymer (e.g., the first polymer and / or the second polymer disclosed herein), and the polymer has a number average molar mass of up to 1 kilodalton (kDa), up to 2 kDa, up to 5 kDa, up to 7 kDa, up to 10 kDa, up to 20 kDa, up to 30 kDa, up to 40 kDa, up to 50 kDa, up to 70 kDa, up to 100 kDa, up to 200 kDa, up to 500 kDa, up to 700 kDa, or up to 1,000 kDa.

[0069] In some embodiments, the biomaterial comprises a polymer (e.g., the first polymer and / or the second polymer disclosed herein), and the polymer has a number average molar mass of about 1 kilodalton (kDa), about 2 kDa, about 5 kDa, about 7 kDa, about 10 kDa, about 20 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 70 kDa, about 100 kDa, about 200 kDa, about 500 kDa, about 700 kDa, or about 1,000 kDa.

[0070] In some embodiments, the biomaterial comprises a first polymer and a second polymer, and the first polymer and the second polymer each have a number average molar mass of at least 0.5 kilodalton (kDa), at least 1 kDa, at least 2 kDa, at least 5 kDa, at least 7 kDa, at least 10 kDa, at least 20 kDa, at least 30 kDa, at least 40 kDa, at least 50 kDa, at least 70 kDa, at least 100 kDa, at least 200 kDa, at least 500 kDa, at least 700 kDa, or at least 1,000 kDa.

[0071] In some embodiments, the biomaterial comprises a first polymer and a second polymer, and the first polymer and the second polymer each have a number average molar mass of up to 1 kilodalton (kDa), up to 2 kDa, up to 5 kDa, up to 7 kDa, up to 10 kDa, up to 20 kDa, up to 30 kDa, up to 40 kDa, up to 50 kDa, up to 70 kDa, up to 100 kDa, up to 200 kDa, up to 500 kDa, up to 700 kDa, or up to 1,000 kDa.

[0072] In some embodiments, the biomaterial comprises a first polymer and a second polymer, and the first polymer and the second polymer each have a number average molar mass of about 1 kilodalton (kDa), about 2 kDa, about 5 kDa, about 7 kDa, about 10 kDa, about 20 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 70 kDa, about 100 kDa, about 200 kDa, about 500 kDa, about 700 kDa, or about 1,000 kDa. Additive.

[0073] In some embodiments, the biomaterial of the present disclosure or a portion thereof can include one or more additives. Non-limiting examples of additives include radiopaque agents, colorants, oils (e.g., silicone), and porogens.

[0074] The density and / or porosity of the polymeric material, and thus the release of therapeutic agents from the surgical article, can be adjusted by including one or more additives, such as porogens, in the polymeric material. In some embodiments, the polymeric material, or at least a portion of the polymeric material, comprises a porogen. The term “porogen” refers to a material that diffuses, dissolves, and / or degrades, leaving pores within the polymeric material. In some embodiments, the 3D printed surgical articles described herein can be printed using at least a portion of a polymeric material that comprises a porogen. Depending on the porogen used, the porogen can then diffuse, dissolve, and / or degrade either before or after implantation, leaving pores in the surgical article. Non-limiting examples of porogens include water-soluble materials such as salts, polysaccharides, water-soluble inorganic materials such as bioactive glasses, silicate-based nanoparticles such as lithium sodium magnesium silicate (Laponite™), and water-soluble or physiologically labile natural or synthetic polymers such as poly(vinylpyrrolidone), pullulan, poly(glycolide), poly(lactide), poly(lactide-co-glycolide), other polyesters, and starch.

[0075] In some embodiments, the porogens of the present disclosure are bioactive glasses, such as ceramics within the Na-Ca-Si-P-O system. In some embodiments, the bioactive glass comprises SiO 2 and CaO. In some embodiments, the bioactive glass further comprises Na 2 O and P 2 O 5 . In some embodiments, the bioactive glass is Bioglass®, bioactive glass 45S5 (45 wt% SiO 2 , 24.5 wt% CaO, 24.5 wt% Na 2 O and 6.0 wt% P 2 O 5 ), bioactive glass 58S, 60 wt% SiO 2 , 36 wt% CaO and 4 wt% P 2 O 5, bioactive glass 70S30C, 70 wt% SiO 2 , and 30 wt% CaO, bioactive glass S53P4, 53 wt% SiO 2 , 23 wt% Na 2 O, 20 wt% CaO and 4 wt% P 2 O 5 (antibacterial), and laponite (Na + 0.7 (Si 8 Mg 5.5 Li 0.3 )O 20 (OH) 4 ) - is selected from.

[0076] In some embodiments, sacrificial ink or fugitive ink can be used to introduce pores or channels into the polymeric material. Non-limiting examples of materials that can act as fugitive ink include poloxamers such as Pluronic® F127, which consists of hydrophobic poly(propylene oxide) (PPO) and hydrophilic poly(ethylene oxide) (PEO) segments arranged in a PEO-PPO-PEO configuration. Therapeutic agent.

[0077] The biomaterials described herein can include a therapeutically effective amount of one or more therapeutic agents. In some embodiments, the therapeutic agent is filled in the solid region of the geometric elements of the biomaterial. In some embodiments, the therapeutic agent(s) may be contained within a boundary (e.g., a porous boundary) forming the end of one or more geometric elements of the article.

[0078] In some embodiments, the one or more therapeutic agents can be selected from anticancer agents, antibacterial agents, antibiotics, local anesthetics or analgesics, statins, and anti-inflammatory agents.

[0079] In some embodiments, the anticancer agent is selected from capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, vinorelbine, and combinations thereof.

[0080] In some embodiments, the antibacterial agent is an antibiotic. In some embodiments, the antibiotic can be a broad-spectrum antibiotic such as gentamicin, clindamycin, and erythromycin, or a Gram-positive and Gram-negative family antibiotic such as ampicillin and cephalosporin. Non-limiting examples of antibiotics suitable for use herein include potassium penicillin V, sodium cloxacillin, sodium dicloxacillin, sodium oxacillin, carbenicillin indanyl sodium, oxytetracycline hydrochloride, tetracycline hydrochloride, clindamycin phosphate, clindamycin hydrochloride, clindamycin HCL palmitate, lincomycin HCL, sodium novobiocin, nitrofurantoin sodium, and metronidazole hydrochloride.

[0081] In some embodiments, the therapeutic agent is a local anesthetic or an analgesic. Non-limiting examples of local anesthetics or analgesics include lidocaine, bupivacaine, tetracaine, ropivacaine, benzocaine, and fentanyl, codeine hydrochloride, codeine phosphate, codeine sulfate, dextromoramide tartrate, hydrocodone bitartrate, hydromorphone hydrochloride, meperidine hydrochloride, methadone hydrochloride, morphine sulfate, morphine acetate, morphine lactate, morphine meconate, morphine nitrate, morphine phosphate, morphine tartrate, morphine valerate, morphine hydrobromide, morphine hydrochloride, and propoxyphene hydrochloride.

[0082] In some embodiments, the therapeutic agent is an anti-inflammatory agent. The anti-inflammatory agent can be selected from non-steroidal anti-inflammatory agents. Non-limiting examples of non-steroidal anti-inflammatory agents include choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, meclofenamic acid sodium, naproxen sodium, and tolmetin sodium. In some implementations, one or more anti-inflammatory substances are selected from non-specific anti-inflammatory agents such as ibuprofen and aspirin, or COX-2 specific inhibitors such as rofecoxib and celecoxib.

[0083] In some embodiments, the therapeutic agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is selected from agents used in the treatment of colorectal cancer. In some embodiments, the anti-cancer agent is selected from gemcitabine (Gemzar™), raltitrexed (Tomudex™), oxaliplatin (Eloxatin™), regorafenib, irinotecan (Camptostar™) and 5-fluorouracil (Adrucil™), and combinations thereof. In some embodiments, the anti-cancer agent is selected from capecitabine, fluorouracil, irinotecan, and oxaliplatin, and combinations thereof.

[0084] In some embodiments, the anti-cancer agent is selected from agents used in the treatment of pancreatic cancer. In some embodiments, the anti-cancer agent is selected from gemcitabine (Gemzar™), fluorouracil (5-FU), irinotecan (Camptosar™), oxaliplatin (Eloxatin™), paclitaxel (Taxol™ or Abraxane™), capecitabine (Xeloda™), cisplatin, docetaxel (Taxotere™) and irinotecan (Onivyde™), and combinations thereof.

[0085] In some embodiments, the anti-cancer agent is selected from agents used in the treatment of lung cancer. In some embodiments, the anti-cancer agent is selected from cisplatin (Platinol™), carboplatin (Paraplatin™), docetaxel (Taxotere™), gemcitabine (Gemzar™), paclitaxel (Taxol™, etc.), vinorelbine (Navelbine™, etc.), pemetrexed (Alimta™), and combinations thereof.

[0086] In some embodiments, the anti-cancer agent is selected from agents used in the treatment of bone cancer. In some embodiments, the anti-cancer agent is selected from doxorubicin (Adriamycin®), cisplatin, etoposide (VP-16), ifosfamide (Ifex®), cyclophosphamide (Cytoxan®), methotrexate and vincristine (Oncovin®), and combinations thereof.

[0087] In some embodiments, the therapeutic agent is a cell (e.g., a human cell). For example, one or more therapeutic agents of the biological material can be selected from pluripotent stem cells, multipotent stem cells, and induced pluripotent stem cells (iPSCs).

[0088] In some embodiments, the biological material comprises a geometric element (e.g., the first or second geometric element disclosed herein), a polymer (e.g., the first or second polymer disclosed herein), and a therapeutic agent, and the amount of the therapeutic agent in the biological material, geometric element, or polymer is at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the weight of the biological material, geometric element, or polymer.

[0089] In some embodiments, the biomaterial includes geometric elements (e.g., the first or second geometric elements disclosed herein), polymers (e.g., the first or second polymers disclosed herein), and the amount of the therapeutic agent in the therapeutic agent, biomaterial, geometric element, or polymer is at most 1%, at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, or at most 95% of the weight of the biomaterial, geometric element, or polymer.

[0090] In some embodiments, the biomaterial includes geometric elements (e.g., the first or second geometric elements disclosed herein), polymers (e.g., the first or second polymers disclosed herein), and a therapeutic agent, and the amount of the therapeutic agent in the biomaterial, geometric element, or polymer is about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the weight of the biomaterial, geometric element, or polymer.

[0091] In some embodiments, the biomaterial includes geometric elements (e.g., the first or second geometric elements disclosed herein), a first polymer, a second polymer, and a therapeutic agent, and the amount of the therapeutic agent in the biomaterial, geometric element, or polymer is at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the combined weight of the first polymer and the second polymer.

[0092] In some embodiments, the biomaterial comprises a geometric element (e.g., the first or second geometric element disclosed herein), a first polymer, a second polymer, and a therapeutic agent, and the amount of the therapeutic agent in the biomaterial, geometric element, or polymer is at most 1%, at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, or at most 95% of the combined weight of the first polymer and the second polymer.

[0093] In some embodiments, the biomaterial comprises a geometric element (e.g., the first or second geometric element disclosed herein), a first polymer, a second polymer, and a therapeutic agent, and the amount of the therapeutic agent in the biomaterial, geometric element, or polymer is about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the combined weight of the first polymer and the second polymer. A method of printing a biomaterial.

[0094] Also disclosed herein is a method for printing the biomaterials of the present disclosure. In some embodiments, the biomaterial is printed using an extrusion-based process. Extrusion-based 3D printing can include any of fused filament fabrication (FFF), fused deposition modeling (FDM), stereolithography, and gel media (with or without particles).

[0095] The printing of the biomaterial can include heating the polymeric material to the melting point of the polymer and creating a suspension of the therapeutic agent in the polymeric material, with or without additional components such as porogens, in combination with the therapeutic agent. The resulting combination, herein referred to as a "slurry", can then be filled into the print head of an extrusion-based 3D printer. The print head can be, for example, a syringe. Variations of this process include, but are not limited to, combining the polymeric material with the therapeutic agent and then heating this combination to the melting point of the polymeric material to form a slurry. Additional components such as porogens can be added at any point during the process. The slurry is extruded onto a substrate along a pre-designed path and the layer-by-layer process is used to form the biomaterial described herein. In some embodiments, a model of the biomaterial is obtained by computer-aided design (CAD).

[0096] In some embodiments, the biomaterials of the present disclosure include multiple layers. Each layer can have a different geometry (e.g., offset, tilted). The layered biomaterial is constructed using a layer-by-layer process to achieve an overall mesh size of, for example, approximately 4 × approximately 6 cm × approximately 0.5 cm (height × width × depth).

[0097] In some embodiments, the biomaterial articles described herein are printed in layers using alternating layers of polymeric material with one or more therapeutic agents dispersed in the polymer and polymeric material without a therapeutic agent. For example, (i) a first layer of polymeric material containing a therapeutic agent dispersed in the polymer, (ii) a second layer of polymeric material without a therapeutic agent (the second layer is disposed on top of the first layer), and (iii) a third layer of polymeric material containing a therapeutic agent dispersed in the polymer (the third layer is disposed on top of the second layer). The layers are printed in this order and repeated until the article reaches the desired thickness. In some implementations, the article can have a thickness in the range of 0.5 - 3.0 cm, or 0.5 - 2.0 cm, or 0.5 - 1.0 cm. Bioprinting Parameters

[0098] The methods disclosed herein can utilize needles in a bioprinting process. In some embodiments, one or more polymer materials, temporary inks, ECM materials, cell suspensions, or combinations thereof are deposited onto a substrate through the needles. The methods of the present disclosure can print from two or more needles, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more needles. In some embodiments, the needles used in the methods disclosed herein have diameters expressed using the Birmingham gauge system. In some embodiments, the needles have a diameter of 7 gauge, 8 gauge, 9 gauge, 10 gauge, 11 gauge, 12 gauge, 13 gauge, 14 gauge, 15 gauge, 16 gauge, 17 gauge, 18 gauge, 19 gauge, 20 gauge, 21 gauge, 22 gauge, 22s gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 26s gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, 33 gauge, or 34 gauge.

[0099] In some embodiments, the needles of the present disclosure have a diameter between 0.1 mm and 400 mm. In some embodiments, the needles of the present disclosure have a diameter between 0.1 mm and 0.5 mm, between 0.1 mm and 1 mm, between 0.1 mm and 10 mm, between 0.1 mm and 20 mm, between 0.1 mm and 30 mm, between 0.1 mm and 40 mm, between 0.1 mm and 50 mm, between 0.1 mm and 100 mm, between 0.1 mm and 200 mm, between 0.1 mm and 300 mm, between 0.1 mm and 400 mm, between 0.5 mm and 1 mm, between 0.5 mm and 10 mm, between 0.5 mm and 20 mm, between 0.5 mm and 30 mm, between 0.5 mm and 40 mm, between 0.5 mm and 50 mm, between 0.5 mm and 100 mm, between 0.5 mm and 200 mm, between 0.5 mm and 300 mm, between 0.5 mm and 400 mm, between 1 mm and 10 mm, between 1 mm and 20 mm, between 1 mm and 30 mm, between 1 mm and 40 mm, between 1 mm and 50 mm, between 1 mm and 100 mm, between 1 mm and 200 mm, between 1 mm and 300 mm, between 1 mm and 400 mm, between 10 mm and 20 mm, between 10 mm and 30 mm, between 10 mm and 40 mm, between 10 mm and 50 mm, between 10 mm and 100 mm, between 10 mm and 200 mm, between 10 mm and 300 mm, between 10 mm and 400 mm, between 20 mm and 30 mm, between 20 mm and 40 mm, between 20 mm and 50 mm, between 20 mm and 100 mm, between 20 mm and 200 mm, between 20 mm and 300 mm, between 20 mm and 400 mm, between 30 mm and 40 mm, between 30 mm and 50 mm, between 30 mm and 100 mm, between 30 mm and 200 mm, between 30 mm and 300 mm, between 30 mm and 400 mm, between 40 mm and 50 mm, between 40 mm and 100 mm, between 40 mm and 200 mm, between 40 mm and 300 mm, between 40 mm and 400 mm, between 50 mm and 100 mm, between 50 mm and 200 mm, between 50 mm and 300 mm, between 50 mm and 400 mm, between 100 mm and 200 mm, between 100 mm and 300 mm, between 100 mm and 400 mm, between 200 mm and 300 mm, between 200 mm and 400 mm, or between 300 mm and 400 mm.In some embodiments, the needles of the present disclosure have a diameter of 0.1 mm, 0.2 mm, 0.5 mm, 1 mm, 10 mm, 20 mm, 30 mm, 40 mm, 50 mm, 100 mm, 200 mm, 300 mm, or 400 mm. In some embodiments, the needles of the present disclosure have a diameter of at least 0.1 mm, at least 0.5 mm, at least 1 mm, at least 10 mm, at least 20 mm, at least 30 mm, at least 40 mm, at least 50 mm, at least 100 mm, at least 200 mm, or at least 300 mm. In some embodiments, the needles of the present disclosure have a diameter of up to 0.5 mm, up to 1 mm, up to 10 mm, up to 20 mm, up to 30 mm, up to 40 mm, up to 50 mm, up to 100 mm, up to 200 mm, up to 300 mm, or up to 400 mm.

[0100] The methods disclosed herein can include passing materials through a needle onto a substrate using an extruder. In some embodiments, one or more materials are deposited onto the substrate by a plurality of extruders. For example, the plurality of extruders can deposit materials simultaneously, sequentially, or in a predetermined order. In some embodiments, the deposition from one or more extruders is controlled in real time. In some embodiments, printing is performed using 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more extruders.

[0101] The temperature at which the extruder operates can be controlled. In some embodiments, the extruder operates at a temperature of about 25°C to about 200°C. In some embodiments, the extruder operates at a temperature of about 25°C to about 37°C, about 25°C to about 50°C, about 25°C to about 75°C, about 25°C to about 100°C, about 25°C to about 150°C, about 25°C to about 200°C, about 27°C to about 37°C, about 27°C to about 50°C, about 27°C to about 75°C, about 27°C to about 100°C, about 27°C to about 150°C, about 27°C to about 200°C, about 37°C to about 50°C, about 37°C to about 75°C, about 37°C to about 100°C, about 37°C to about 150°C, about 37°C to about 200°C, about 50°C to about 75°C, about 50°C to about 100°C, about 50°C to about 150°C, about 50°C to about 200°C, about 75°C to about 100°C, about 75°C to about 150°C, about 75°C to about 200°C, about 100°C to about 150°C, about 100°C to about 200°C, or about 150°C to about 200°C. In some embodiments, the extruder operates at a temperature of about 25°C, about 27°C, about 37°C, about 50°C, about 65°C, about 75°C, about 100°C, about 150°C, or about 200°C. In some embodiments, the extruder operates at a temperature of at least about 25°C, at least about 27°C, at least about 37°C, at least about 50°C, at least about 75°C, at least about 100°C, or at least about 150°C. In some embodiments, the extruder operates at a temperature of at most about 25°C, at most about 37°C, at most about 50°C, at most about 75°C, at most about 100°C, at most about 150°C, or at most about 200°C.

[0102] In some embodiments, pressurized air is used to pass the material through an extruder. The air pressure of the extruder can be controlled. In some embodiments, the extruder operates at an air pressure of about 600 kPa to about 800 kPa. In some embodiments, the extruder operates at an air pressure of about 600 kPa to about 625 kPa, about 600 kPa to about 650 kPa, about 600 kPa to about 675 kPa, about 600 kPa to about 700 kPa, about 600 kPa to about 725 kPa, about 600 kPa to about 750 kPa, about 600 kPa to about 775 kPa, about 600 kPa to about 800 kPa, about 625 kPa to about 650 kPa, about 625 kPa to about 675 kPa, about 625 kPa to about 700 kPa, about 625 kPa to about 725 kPa, about 625 kPa to about 750 kPa, about 625 kPa to about 775 kPa, about 625 kPa to about 800 kPa, about 650 kPa to about 675 kPa, about 650 kPa to about 700 kPa, about 650 kPa to about 725 kPa, about 650 kPa to about 750 kPa, about 650 kPa to about 775 kPa, about 650 kPa to about 800 kPa, about 675 kPa to about 700 kPa, about 675 kPa to about 725 kPa, about 675 kPa to about 750 kPa, about 675 kPa to about 775 kPa, about 675 kPa to about 800 kPa, about 700 kPa to about 725 kPa, about 700 kPa to about 750 kPa, about 700 kPa to about 775 kPa, about 700 kPa to about 800 kPa, about 725 kPa to about 750 kPa, about 725 kPa to about 775 kPa, about 725 kPa to about 800 kPa, about 750 kPa to about 775 kPa, about 750 kPa to about 800 kPa, or about 775 kPa to about 800 kPa. In some embodiments, the extruder operates at an air pressure of about 600 kPa, about 625 kPa, about 650 kPa, about 675 kPa, about 689.5 kPa, about 700 kPa, about 717.1 kPa, about 725 kPa, about 750 kPa, about 775 kPa, or about 800 kPa. In some embodiments, the extruder operates at an air pressure of at least about 600 kPa, at least about 625 kPa, at least about 650 kPa, at least about 675 kPa, at least about 700 kPa, at least about 725 kPa, at least about 750 kPa, or at least about 775 kPa.In some embodiments, the extruder operates at an air pressure of up to about 625 kPa, up to about 650 kPa, up to about 675 kPa, up to about 700 kPa, up to about 725 kPa, up to about 750 kPa, up to about 775 kPa, or up to about 800 kPa.

[0103] In some embodiments, the extruder operates at an air pressure of about 60 pounds per square inch (psi) to about 120 psi. In some embodiments, the extruder operates at an air pressure of about 87 psi to about 90.6 psi, about 87 psi to about 94.3 psi, about 87 psi to about 97.9 psi, about 87 psi to about 101.5 psi, about 87 psi to about 105.2 psi, about 87 psi to about 108.8 psi, about 87 psi to about 112.4 psi, about 87 psi to about 116 psi, about 90.6 psi to about 94.3 psi, about 90.6 psi to about 97.9 psi, about 90.6 psi to about 101.5 psi, about 90.6 psi to about 105.2 psi, about 90.6 psi to about 108.8 psi, about 90.6 psi to about 112.4 psi, about 90.6 psi to about 116 psi, about 94.3 psi to about 97.9 psi, about 94.3 psi to about 101.5 psi, about 94.3 psi to about 105.2 psi, about 94.3 psi to about 108.8 psi, about 94.3 psi to about 112.4 psi, about 94.3 psi to about 116 psi, about 97.9 psi to about 101.5 psi, about 97.9 psi to about 105.2 psi, about 97.9 psi to about 108.8 psi, about 97.9 psi to about 112.4 psi, about 97.9 psi to about 116 psi, about 101.5 psi to about 105.2 psi, about 101.5 psi to about 108.8 psi, about 101.5 psi to about 112.4 psi, about 101.5 psi to about 116 psi, about 105.2 psi to about 108.8 psi, about 105.2 psi to about 112.4 psi, about 105.2 psi to about 116 psi, about 108.8 psi to about 112.4 psi, about 108.8 psi to about 116 psi, or about 112.4 psi to about 116 psi. In some embodiments, the extruder operates at an air pressure of about 60 psi, about 87 psi, about 90.6 psi, about 94.3 psi, about 97.9 psi, about 100 psi, about 101.5 psi, about 104 psi, about 105.2 psi, about 108.8 psi, about 112.4 psi, about 116 psi, or about 120 psi.In some embodiments, the extruder operates at an air pressure of at least about 60 psi, at least about 87 psi, at least about 90.6 psi, at least about 94.3 psi, at least about 97.9 psi, at least about 101.5 psi, at least about 105.2 psi, at least about 108.8 psi, or at least about 112.4 psi. In some embodiments, the extruder operates at an air pressure of up to about 90.6 psi, up to about 94.3 psi, up to about 97.9 psi, up to about 101.5 psi, up to about 105.2 psi, up to about 108.8 psi, up to about 112.4 psi, up to about 116 psi, or up to about 120 psi.

[0104] The method of the present disclosure can include printing the material at various linear extrusion speeds. In some embodiments, the material is deposited at a linear extrusion speed of from about 8 mm / sec to about 800 mm / sec. In some embodiments, the material is from about 100 mm / sec to about 150 mm / sec, from about 100 mm / sec to about 200 mm / sec, from about 100 mm / sec to about 250 mm / sec, from about 100 mm / sec to about 300 mm / sec, from about 100 mm / sec to about 350 mm / sec, from about 100 mm / sec to about 400 mm / sec, from about 100 mm / sec to about 450 mm / sec, from about 100 mm / sec to about 500 mm / sec, from about 100 mm / sec to about 600 mm / sec, from about 100 mm / sec to about 700 mm / sec, from about 100 mm / sec to about 800 mm / sec, from about 150 mm / sec to about 200 mm / sec, from about 150 mm / sec to about 250 mm / sec, from about 150 mm / sec to about 300 mm / sec, from about 150 mm / sec to about 350 mm / sec, from about 150 mm / sec to about 400 mm / sec, from about 150 mm / sec to about 450 mm / sec, from about 150 mm / sec to about 500 mm / sec, from about 150 mm / sec to about 600 mm / sec, from about 150 mm / sec to about 700 mm / sec, from about 150 mm / sec to about 800 mm / sec, from about 200 mm / sec to about 250 mm / sec, from about 200 mm / sec to about 300 mm / sec, from about 200 mm / sec to about 350 mm / sec, from about 200 mm / sec to about 400 mm / sec, from about 200 mm / sec to about 450 mm / sec, from about 200 mm / sec to about 500 mm / sec, from about 200 mm / sec to about 600 mm / sec, from about 200 mm / sec to about 700 mm / sec, from about 200 mm / sec to about 800 mm / sec, from about 250 mm / sec to about 300 mm / sec, from about 250 mm / sec to about 350 mm / sec, from about 250 mm / sec to about 400 mm / sec, from about 250 mm / sec to about 450 mm / sec, from about 250 mm / sec to about 500 mm / sec, from about 250 mm / sec to about 600 mm / sec, from about 250 mm / sec to about 700 mm / sec, from about 250 mm / sec to about 800 mm / sec, from about 300 mm / sec to about 350 mm / sec, from about 300 mm / sec to about 400 mm / sec, from about 300 mm / sec to about 450 mm / sec, from about 300 mm / sec to about 500 mm / sec, from about 300 mm / sec to about 600 mm / sec, from about 300 mm / sec to about 700 mm / sec, from about 300 mm / sec to about 800 mm / sec, from about 350 mm / sec to about 400 mm / sec, from about 350 mm / sec to about 450 mm / sec, from about 350 mm / sec to about 500 mm / sec, from about 350 mm / sec to about 600 mm / sec, from about 350 mm / sec to about 700 mm / sec,Deposited at a linear extrusion speed of about 350 mm / sec to about 800 mm / sec, about 400 mm / sec to about 450 mm / sec, about 400 mm / sec to about 500 mm / sec, about 400 mm / sec to about 600 mm / sec, about 400 mm / sec to about 700 mm / sec, about 400 mm / sec to about 800 mm / sec, about 450 mm / sec to about 500 mm / sec, about 450 mm / sec to about 600 mm / sec, about 450 mm / sec to about 700 mm / sec, about 450 mm / sec to about 800 mm / sec, about 500 mm / sec to about 600 mm / sec, about 500 mm / sec to about 700 mm / sec, about 500 mm / sec to about 800 mm / sec, about 600 mm / sec to about 700 mm / sec, about 600 mm / sec to about 800 mm / sec, or about 700 mm / sec to about 800 mm / sec. In some embodiments, the material is at about 8 mm / sec, about 10 mm / sec, about 100 mm / sec, about 150 mm / sec, about 200 mm / sec, about 250 mm / sec, about 300 mm / sec, about 350 mm / sec, about 400 mm / sec, about 450 mm / sec, about 500 mm / sec, about 600 mm / sec, about 700 mm / sec, or about 800 mm / sec. In some embodiments, the material is deposited at a linear extrusion speed of at least about 8 mm / sec, at least about 100 mm / sec, at least about 150 mm / sec, at least about 200 mm / sec, at least about 250 mm / sec, at least about 300 mm / sec, at least about 350 mm / sec, at least about 400 mm / sec, at least about 450 mm / sec, at least about 500 mm / sec, at least about 600 mm / sec, or at least about 700 mm / sec. In some embodiments, the material is deposited at a linear extrusion speed of at most about 150 mm / sec, at most about 200 mm / sec, at most about 250 mm / sec, at most about 300 mm / sec, at most about 350 mm / sec, at most about 400 mm / sec, at most about 450 mm / sec, at most about 500 mm / sec, at most about 600 mm / sec, at most about 700 mm / sec, or at most about 800 mm / sec.,

[0105] The method of the present disclosure can include printing a material at various volumetric rates. In some embodiments, the printing is performed at a volumetric rate of from about 1 μL / sec to about 100 μL / sec. In some embodiments, the printing is at a volumetric rate of about 1 μL / sec to about 5 μL / sec, about 1 μL / sec to about 10 μL / sec, about 1 μL / sec to about 15 μL / sec, about 1 μL / sec to about 20 μL / sec, about 1 μL / sec to about 25 μL / sec, about 1 μL / sec to about 50 μL / sec, about 1 μL / sec to about 100 μL / sec, about 5 μL / sec to about 10 μL / sec, about 5 μL / sec to about 15 μL / sec, about 5 μL / sec to about 20 μL / sec, about 5 μL / sec to about 25 μL / sec, about 5 μL / sec to about 50 μL / sec, about 5 μL / sec to about 100 μL / sec, about 10 μL / sec to about 15 μL / sec, about 10 μL / sec to about 20 μL / sec, about 10 μL / sec to about 25 μL / sec, about 10 μL / sec to about 50 μL / sec, about 10 μL / sec to about 100 μL / sec, about 15 μL / sec to about 20 μL / sec, about 15 μL / sec to about 25 μL / sec, about 15 μL / sec to about 50 μL / sec, about 15 μL / sec to about 100 μL / sec, about 20 μL / sec to about 25 μL / sec, about 20 μL / sec to about 50 μL / sec, about 20 μL / sec to about 100 μL / sec, about 25 μL / sec to about 50 μL / sec, about 25 μL / sec to about 100 μL / sec, or about 50 μL / sec to about 100 μL / sec. In some embodiments, the printing is performed at a volumetric rate of about 1 μL / sec, about 5 μL / sec, about 10 μL / sec, about 15 μL / sec, about 20 μL / sec, about 25 μL / sec, about 50 μL / sec, or about 100 μL / sec. In some embodiments, the printing is performed at a volumetric rate of at least about 1 μL / sec, at least about 5 μL / sec, at least about 10 μL / sec, at least about 15 μL / sec, at least about 20 μL / sec, at least about 25 μL / sec, or at least about 50 μL / sec. In some embodiments, the printing is performed at a volumetric rate of at most about 5 μL / sec, at most about 10 μL / sec, at most about 15 μL / sec, at most about 20 μL / sec, at most about 25 μL / sec, at most about 50 μL / sec, or at most about 100 μL / sec.

[0106] The method of the present disclosure can include controlling the deposition of a material (e.g., a polymer) at a certain resolution. In some embodiments, the methods disclosed herein can include controlling the deposition of the material at a resolution of from about 0.01 mm to about 1 mm. In some embodiments, the methods disclosed herein can include controlling the deposition of the material at a resolution of from about 0.01 mm to about 0.05 mm, from about 0.01 mm to about 0.1 mm, from about 0.01 mm to about 0.2 mm, from about 0.01 mm to about 0.3 mm, from about 0.01 mm to about 0.4 mm, from about 0.01 mm to about 0.5 mm, from about 0.01 mm to about 1 mm, from about 0.05 mm to about 0.1 mm, from about 0.05 mm to about 0.2 mm, from about 0.05 mm to about 0.3 mm, from about 0.05 mm to about 0.4 mm, from about 0.05 mm to about 0.5 mm, from about 0.05 mm to about 1 mm, from about 0.1 mm to about 0.2 mm, from about 0.1 mm to about 0.3 mm, from about 0.1 mm to about 0.4 mm, from about 0.1 mm to about 0.5 mm, from about 0.1 mm to about 1 mm, from about 0.2 mm to about 0.3 mm, from about 0.2 mm to about 0.4 mm, from about 0.2 mm to about 0.5 mm, from about 0.2 mm to about 1 mm, from about 0.3 mm to about 0.4 mm, from about 0.3 mm to about 0.5 mm, from about 0.3 mm to about 1 mm, from about 0.4 mm to about 0.5 mm, from about 0.4 mm to about 1 mm, or from about 0.5 mm to about 1 mm. In some embodiments, the methods disclosed herein can include a resolution of about 0.01 mm, about 0.05 mm, about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, or about 1 mm. In some embodiments, the methods disclosed herein can include controlling the deposition of the material at a resolution of at least about 0.01 mm, at least about 0.05 mm, at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, or at least about 0.5 mm. In some embodiments, the methods disclosed herein can include controlling the deposition of the material at a resolution of up to about 0.05 mm, up to about 0.1 mm, up to about 0.2 mm, up to about 0.3 mm, up to about 0.4 mm, up to about 0.5 mm, or up to about 1 mm. Computer system

[0107] Bioprinting parameters, such as deposition rate, extruder pressure, extruder temperature, extruder deposition pattern, deposition location, layer thickness, and the material being deposited, etc., can be controlled by a computer system. In some embodiments, the computer system includes a processor, a memory device, an operating system, and software modules for monitoring or operating the extruder. In some embodiments, the computer system includes a digital processing device and includes one or more hardware central processing units (CPUs). In further embodiments, the computer system includes an operating system configured to execute executable instructions. In some embodiments, the operating system is software including programs and data that manages the hardware of the device and provides services for the execution of applications. Suitable server operating systems include, by way of non-limiting example, FreeBSD, OpenBSD, NetBSD®, Linux®, Apple® Mac OS X Server®, Oracle® Solaris®, Windows Server®, and Novell® NetWare®. Suitable personal computer operating systems include, by way of non-limiting example, Microsoft® Windows®, Apple® Mac OS X®, UNIX®, UNIX®-like operating systems such as GNU / Linux®. In some embodiments, the operating system is provided by cloud computing. In some embodiments, a mobile smartphone operating system is used.Non-limiting examples of mobile smartphone operating systems include Nokia® Symbian® OS, Apple® iOS®, Research In Motion® BlackBerryOS®, Google° Android®, Microsoft® Windows Phone® OS, Microsoft® Windows Mobile® OS, Linux®, and Palm® WebOS. In some embodiments, the computer system includes a storage and / or memory device. In some embodiments, the storage and / or memory device is one or more physical devices used to temporarily or permanently store data or programs. In some embodiments, the device is volatile memory and requires power to maintain the stored information. In some embodiments, the device is non-volatile memory and retains the stored information when power is not supplied to the digital processing device. In further embodiments, the non-volatile memory includes flash memory. In some embodiments, the non-volatile memory includes dynamic random access memory (DRAM). In some embodiments, the non-volatile memory includes ferroelectric random access memory (FRAM®). In some embodiments, the non-volatile memory includes phase change random access memory (PRAM). In some embodiments, the device is a storage device including, as non-limiting examples, CD-ROM, DVD, flash memory devices, magnetic disk drives, magnetic tape drives, optical disk drives, and cloud computing-based storage. In some embodiments, the storage and / or memory device is a combination of devices such as those disclosed herein.

[0108] In some embodiments, the computer system described herein includes a user interface. In further embodiments, the user interface includes a graphical user interface (GUI), such as the Repetier-Host graphical user interface. In some embodiments, the user interface is interactive and presents the user with menus and options for interacting with the computer system and the delivery system described herein. In some embodiments, the computer system includes a display screen for transmitting visual information to the user. In some embodiments, the display is a cathode ray tube (CRT). In some embodiments, the display is a liquid crystal display (LCD). In further embodiments, the display is a thin film transistor liquid crystal display (TFT-LCD). In some embodiments, the display is an organic light emitting diode (OLED) display. In some embodiments, the OLED display is a passive matrix OLED (PMOLED) or an active matrix OLED (AMOLED) display. In some embodiments, the display is a plasma display. In some embodiments, the display is a video projector. In some embodiments, the display is a combination of displays, such as those disclosed herein. In some embodiments, the device includes an input device for receiving information from the user. In some embodiments, the input device is a keyboard. In some embodiments, the input device is a keypad. In some embodiments, the input device is a display screen that is a touch screen or a multi-touch screen. In some embodiments, the input device is a microphone for capturing voice or other sound inputs. In some embodiments, the systems and software modules disclosed herein are intranet-based. In some embodiments, the systems and software modules are internet-based. In some embodiments, the computer system and software modules are world wide web-based.In some embodiments, the computer system and software modules are cloud computing-based. In some embodiments, the computer system and software modules are based on data storage devices including, by way of non-limiting example, CD-ROMs, DVDs, flash memory devices, RAM (e.g., DRAM, SRAM, etc.), ROM (e.g., PROM, EPROM, EEPROM, etc.), magnetic tape drives, magnetic disk drives, optical disk drives, magneto-optical drives, solid state drives, and combinations thereof. Method of use.

[0109] The biomaterials described herein can control and sustain in situ the release of one or more therapeutic agents at a target site within the body of a subject in need of treatment of a disease, disorder, or condition treatable by one or more therapeutic agents. The release of one or more therapeutic agents from the implanted article can occur by several mechanisms including, but not limited to, diffusion through the polymeric material, diffusion by transport through pores or channels filled with a liquid within the polymeric material, and diffusion by degradation of the polymeric material.

[0110] Some of the structural features of the biomaterials disclosed herein can be adapted to modify the release of the therapeutic agent(s) from the biomaterial. These structural features include, but are not limited to, the composition of the polymeric material, the density and / or porosity of the polymeric material, the size, shape, and number and arrangement of defined geometric elements that form a pattern of defined geometric elements, and the sub-structure of the unit biomaterial (e.g., a laminated biomaterial).

[0111] The macro three-dimensional configuration of the biomaterial of the present disclosure can also be adapted to modify the release of the therapeutic agent(s) and / or to concentrate the release in a particular part or region of the article. For example, the biomaterial can be folded or rolled up for insertion into the target site. Some unit biomaterials can also be formed or printed into stacked layers having a desired orientation including a misaligned configuration. In some embodiments, the article can be coated with a coating. In some embodiments, the coating prevents burst release when the biomaterial is placed in situ. For example, the biomaterial can be coated with the same drug using a dip coating method, which is a standard method used in pharmaceutical research and drug development. Dip coating of the article can be achieved by immersing the biomaterial in a polymer-drug solution and then drying the biomaterial to create a thin, uniform coating. Alternatively, the biomaterial can be coated using a spray, which may enable the direct spraying of microdroplets of the therapeutic agent onto the biomaterial itself. In some embodiments, the above combinations can be used to coat the biomaterial using a hybrid method.

[0112] In some embodiments, the biomaterial releases one or more therapeutic agents over a period of about 1 day to about 1 week, about 1 week to about 1 month, about 1 month to about 2 months, about 2 months to about 6 months, about 6 months to about 12 months, about 12 months to about 24 months, about 24 months to about 42 months, about 24 months to about 54 months, or about 24 months to about 60 months. In some embodiments, the biomaterial releases one or more therapeutic agents over a period of about 24 months, about 30 months, about 36 months, about 42 months, about 54 months, or about 60 months. In some embodiments, the biomaterial releases one or more therapeutic agents over a period of at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 54 months, or at least about 60 months. In some embodiments, the biomaterial releases one or more therapeutic agents over a period of up to about 24 months, up to about 30 months, up to about 36 months, up to about 42 months, up to about 54 months, or up to about 60 months.

[0113] Non-limiting examples of subjects include humans, primates, mice, rats, dogs, cats, cows, horses, goats, camels, sheep, or pigs. In some embodiments, the methods disclosed herein are methods of treating a subject in need thereof.

[0114] In some embodiments, transplantation of the biomaterials of the present disclosure can deliver a therapeutically effective amount of one or more therapeutic agents to a target site in situ over a period of time.

[0115] The methods disclosed herein can treat a condition, for example, by reducing, alleviating, or reducing the likelihood of one or more symptoms or complications of a disease or disorder. In some embodiments, the methods disclosed herein reduce the likelihood of a disease or disorder occurring in a subject. For example, in the context of cancer, treatment of cancer can include slowing cancer growth, slowing or preventing the occurrence of metastasis or further metastasis, and promoting regression of one or more tumors in the subject being treated.

[0116] In some embodiments, the biomaterial is used to release a drug over a period of, for example, about 3 weeks, about 4 weeks, about 30 days, or about 5 weeks. During this period, for example, about 40% (e.g., + / - 10%), 50% (e.g., + / - 10%), 55% (e.g., + / - 10%), 60% (e.g., + / - 10%), 65% (e.g., + / - 10%), 70% (e.g., + / - 10%), 75% (e.g., + / - 10%), 80% (e.g., + / - 10%), or 85% (e.g., + / - 10%) of the drug can be released from the biomaterial. For example, when approximately 75% of a 20 mg dose of 5-FU is released, a therapeutic dose of 15 mg can be delivered.

[0117] In some embodiments, the biomaterial releases about 40% (e.g., + / - 10%), about 50% (e.g., + / - 10%), about 55% (e.g., + / - 10%), about 60% (e.g., + / - 10%), about 65% (e.g., + / - 10%), about 70% (e.g., + / - 10%), about 75% (e.g., + / - 10%), about 80% (e.g., + / - 10%), or about 85% (e.g., + / - 10%) of the drug over a 3-week period. In some embodiments, the biomaterial releases about 40% (e.g., + / - 10%), about 50% (e.g., + / - 10%), about 55% (e.g., + / - 10%), about 60% (e.g., + / - 10%), about 65% (e.g., + / - 10%), about 70% (e.g., + / - 10%), about 75% (e.g., + / - 10%), about 80% (e.g., + / - 10%), or about 85% (e.g., + / - 10%) of the drug over a 4-week period. In some embodiments, the biomaterial releases about 40% (e.g., + / - 10%), about 50% (e.g., + / - 10%), about 55% (e.g., + / - 10%), about 60% (e.g., + / - 10%), about 65% (e.g., + / - 10%), about 70% (e.g., + / - 10%), about 75% (e.g., + / - 10%), about 80% (e.g., + / - 10%), or about 85% (e.g., + / - 10%) of the drug over a 5-week period. In some embodiments, the biomaterial releases about 40% (e.g., + / - 10%), about 50% (e.g., + / - 10%), about 55% (e.g., + / - 10%), about 60% (e.g., + / - 10%), about 65% (e.g., + / - 10%), about 70% (e.g., + / - 10%), about 75% (e.g., + / - 10%), about 80% (e.g., + / - 10%), or about 85% (e.g., + / - 10%) of the drug over a 30-day period.

[0118] In some embodiments, the biomaterial releases at least about 40% (e.g., + / - 10%), at least about 50% (e.g., + / - 10%), at least about 55% (e.g., + / - 10%), at least about 60% (e.g., + / - 10%), at least about 65% (e.g., + / - 10%), at least about 70% (e.g., + / - 10%), at least about 75% (e.g., + / - 10%), at least about 80% (e.g., + / - 10%), or at least about 85% (e.g., + / - 10%) of the drug over a period of 3 weeks. In some embodiments, the biomaterial releases at least about 40% (e.g., + / - 10%), at least about 50% (e.g., + / - 10%), at least about 55% (e.g., + / - 10%), at least about 60% (e.g., + / - 10%), at least about 65% (e.g., + / - 10%), at least about 70% (e.g., + / - 10%), at least about 75% (e.g., + / - 10%), at least about 80% (e.g., + / - 10%), or at least about 85% (e.g., + / - 10%) of the drug over a period of 4 weeks. In some embodiments, the biomaterial releases at least about 40% (e.g., + / - 10%), at least about 50% (e.g., + / - 10%), at least about 55% (e.g., + / - 10%), at least about 60% (e.g., + / - 10%), at least about 65% (e.g., + / - 10%), at least about 70% (e.g., + / - 10%), at least about 75% (e.g., + / - 10%), at least about 80% (e.g., + / - 10%), or at least about 85% (e.g., + / - 10%) of the drug over a period of 5 weeks. In some embodiments, the biomaterial releases at least about 40% (e.g., + / - 10%), at least about 50% (e.g., + / - 10%), at least about 55% (e.g., + / - 10%), at least about 60% (e.g., + / - 10%), at least about 65% (e.g., + / - 10%), at least about 70% (e.g., + / - 10%), at least about 75% (e.g., + / - 10%), at least about 80% (e.g., + / - 10%), or at least about 85% (e.g., + / - 10%) of the drug over a period of 30 days.

[0119] In some embodiments, a single dose is administered. For example, one or more biological materials are administered and, if necessary, removed, for example, 4 weeks after transplantation. In some embodiments, repeated doses are administered. For example, one or more biological materials are administered and, if necessary, removed (e.g., 4 weeks after transplantation), and then one or more biological materials are administered a second time (e.g., approximately 30 days after the first administration). In some embodiments, the repeated doses are administered, for example, every about 4 weeks (e.g., ±5 days), every about 30 days (e.g., ±5 days), every about 45 days (e.g., ±5 days), or every about 60 days (e.g., ±5 days).

[0120] In some embodiments, the biomaterial comprises a drug (e.g., an active pharmaceutical ingredient (API), e.g., 5-FU) at a dosage of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, or about 180 mg as disclosed herein. In some embodiments, the biomaterial comprises a drug at a dosage of about 10 - 180 mg, about 20 - 180 mg, about 20 - 100 mg, about 10 - 60 mg, about 20 - 60 mg, about 20 - 40 mg, or about 15 - 30 mg. In some embodiments, the biomaterial comprises a drug at a dosage of at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, or at least about 180 mg. In some embodiments, the biomaterial comprises a drug at a dosage of up to about 10 mg, up to about 15 mg, up to about 20 mg, up to about 25 mg, up to about 30 mg, up to about 40 mg, up to about 60 mg, up to about 80 mg, up to about 100 mg, up to about 120 mg, up to about 140 mg, up to about 160 mg, or up to about 180 mg. In some embodiments, the biomaterial comprises a dosage in one biomaterial unit (e.g., a chip) as disclosed herein. In some embodiments, the dosage is divided among 2, 3, 4, or 5 biomaterial units (e.g., chips). The multiple units may be separate or joined together (e.g., sutured).

[0121] The biomaterials disclosed herein can limit systemic exposure to a therapeutic agent (e.g., a drug). In some embodiments, the level of the drug in the circulation (e.g., blood or plasma) of a subject to whom the biomaterial is applied locally is at most 25%, at most 20%, at most 15%, at most 10%, at most 5%, or at most 1% of the level in a subject to whom the therapeutic agent is administered by a systemic route (e.g., intravenously). The biomaterials disclosed herein can limit systemic exposure to a therapeutic agent (e.g., a drug). In some embodiments, the level of the drug in the circulation (e.g., blood or plasma) of a subject to whom the biomaterial is applied locally is at most 50%, at most 25%, at most 20%, at most 15%, at most 10%, at most 5%, or at most 1% of the level in a subject to whom the therapeutic agent is administered locally. A method of treating cancer.

[0122] The present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising implanting a biomaterial of the present disclosure into a target site of the subject. In some embodiments, the target site is part of an organ, hard tissue, soft tissue, or lymph node. In some embodiments, the target site is a solid tumor or a part thereof. As described above, the surgical article can be filled with an effective amount of one or more therapeutic agents to provide a therapeutic dose of one or more agents at the in-situ target site over a period ranging from weeks to months, years.

[0123] In some embodiments, the subject in need of treatment is a cancer, such as colorectal cancer, anal cancer, esophageal cancer, gastric cancer, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, laryngeal cancer, gallbladder cancer, pancreatic cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, nerve tissue cancer, head and neck cancer, colon cancer, stomach cancer, bronchial cancer, kidney cancer, basal cell carcinoma, squamous cell carcinoma of both ulcerative and papillary types, metastatic skin cancer, osteosarcoma, Ewing's sarcoma, reticulum cell sarcoma, myeloma, giant cell tumor, small cell lung tumor, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuroma, enteric ganglioneuroma, hyperplastic corneal nerve tumor, Marfanoid body tumor, Wilms' tumor, seminoma, ovarian tumor, cervical dysplasia and intraepithelial carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, fungating polyposis, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcomas, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforme, leukemia, lymphoma, malignant melanoma, epidermoid carcinoma, carcinoma, sarcoma, hemangioma, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuroma, neurofibroma, bile duct adenoma, bile duct cystadenoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, and a human patient diagnosed with nodular regenerative hyperplasia.

[0124] In some embodiments, the cancer is metastatic. In some embodiments, the cancer is non-metastatic. In some embodiments, the cancer is an advanced local cancer. In some embodiments, the cancer is a recurrent locally advanced cancer.

[0125] In some embodiments, the biological materials disclosed herein can be used to treat subjects having malignant cancer or end-stage cancer. In some embodiments, the subject in need of treatment may be non-responsive or refractory to currently available treatments, or the disease, disorder or condition being treated, such as standard care treatments for cancer.

[0126] In some embodiments, the biomaterials disclosed herein can be used to treat colorectal cancer, such as colon cancer, rectal cancer, or intestinal cancer, gastrointestinal malignancies, or any cancer that occurs in the colon or rectum. In some embodiments, the biomaterial for treating colon cancer comprises a therapeutic agent adapted for the treatment of colon cancer. In some embodiments, the biomaterial comprises a therapeutic agent selected from one or more of gemcitabine (Gemzar), raltitrexed (Tomudex™), oxaliplatin (Eloxatin™), regorafenib, irinotecan (Camptostar™), and 5-fluorouracil (Adrucil™). In some embodiments, the therapeutic agent is selected from capecitabine, fluorouracil, irinotecan, and oxaliplatin, and combinations thereof.

[0127] In some embodiments, treating cancer according to the methods described herein eliminates the symptoms or complications of the cancer being treated. Elimination of symptoms is not required. In some embodiments, the severity of the symptoms is reduced. In the context of cancer, non-limiting examples of such symptoms include the degree to which the tumor secretes growth factors, degrades the extracellular matrix, undergoes angiogenesis, loses adhesion to adjacent tissues, or metastasizes, and the number of metastases, as well as clinical markers of severity or progression.

[0128] By treating cancer according to the methods described herein, the size of the tumor can be reduced. The reduction in the size of the tumor is also referred to as tumor regression. In some embodiments, the tumor size is reduced by at least about 5% after treatment as compared to the size of the tumor before treatment. In some embodiments, the tumor size is reduced by at least about 10% after treatment. In some embodiments, the tumor size is reduced by at least about 20% after treatment. In some embodiments, the tumor size is reduced by at least about 30% after treatment. In some embodiments, the tumor size is reduced by at least about 40% after treatment. In some embodiments, the tumor size is reduced by at least about 50% after treatment. In some embodiments, the tumor size is reduced by at least about 75% after treatment. In some embodiments, the size of the tumor can be measured as the diameter of the tumor.

[0129] By treating cancer according to the methods described herein, the tumor volume can be reduced. In some embodiments, the tumor volume is reduced by at least about 5% after treatment as compared to the size of the tumor before treatment. In some embodiments, the tumor volume is reduced by at least about 10% after treatment. In some embodiments, the tumor volume is reduced by at least about 20% after treatment. In some embodiments, the tumor volume is reduced by at least about 30% after treatment. In some embodiments, the tumor volume is reduced by at least about 40% after treatment. In some embodiments, the tumor volume is reduced by at least about 50% after treatment. In some embodiments, the tumor volume is reduced by at least about 75% after treatment. In some embodiments, the tumor volume is reduced by at least about 60% to at least about 90% after treatment.

[0130] Treating cancer according to the methods described herein can reduce the number of tumors. The number of tumors can be reduced by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 75% compared to, for example, the number of tumors before treatment. The number of tumors can be measured by any reproducible measurement. The number of tumors can be measured by visually counting the tumors or by viewing the tumors at a specific magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x magnification).

[0131] Treating cancer according to the methods described herein can reduce the number of metastatic lesions in tissues or organs other than the primary tumor site. The metastatic lesions can be reduced by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 75% compared to, for example, the number of metastatic lesions before treatment. The number of metastatic lesions can be measured by any reproducible measurement. The number of tumors can be measured by visually counting the tumors or by viewing the tumors at a specific magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x magnification).

[0132] Treating cancer according to the methods described herein can extend the mean survival time of a population of treated subjects compared to a population receiving the carrier alone. The extension of the mean survival time of the population can be measured by any reproducible method. The extension of the mean survival time of the population can be measured, for example, by calculating the mean survival time for the population after the start of treatment with the active compound (e.g., transplantation of a biomaterial loaded with a therapeutic agent). The extension of the mean survival time of the population can also be measured, for example, by calculating the mean survival time for the population after completion of the first round of treatment with the active compound. In some embodiments, the mean survival time of the population is extended by at least 30 days, at least 60 days, at least 90 days, or at least 120 days.

[0133] By treating cancer according to the methods described herein, the average survival period of the treated population of subjects can be extended compared to a population receiving standard care treatment. In some embodiments, the average survival period of the population is extended by at least 30 days, at least 60 days, at least 90 days, or at least 120 days. The extension of the average survival period of the population can be measured by any reproducible method. The extension of the average survival period of the population can be measured, for example, by calculating the average survival period for the population after the initiation of treatment with an active compound (e.g., transplantation of a biomaterial loaded with a therapeutic agent). The extension of the average survival period of the population can also be measured, for example, by calculating the average survival period for the population after the completion of a first round of treatment with an active compound.

[0134] By treating cancer according to the methods described herein, the mortality rate of the treated population of subjects can be decreased compared to a population receiving a carrier alone. By treating cancer according to the methods described herein, the mortality rate of the treated population of subjects can be decreased compared to an untreated population. By treating cancer according to the methods described herein, the mortality rate of the treated population of subjects can be decreased compared to a population receiving standard care treatment. For example, the mortality rate can be decreased by at least about 2%, at least about 5%, at least about 10%, or at least about 25%. The decrease in the mortality rate of the treated population of subjects can be measured by any reproducible method. The decrease in the mortality rate of the population can be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after the initiation of treatment with an active compound. The decrease in the mortality rate of the population can also be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after the completion of a first round of treatment with an active compound.

[0135] By treating cancer according to the methods described herein, the tumor growth rate can be decreased. In some embodiments, the methods disclosed herein decrease the tumor growth rate by at least about 5%, at least about 10%, at least about 30%, at least about 40%, at least about 50%, or at least about 75% compared to the pre-treatment number. The tumor growth rate can be measured by any reproducible measurement. The tumor growth rate can be measured according to the change in tumor diameter per unit time. In some embodiments, after treatment, the tumor growth rate can be made substantially zero and it is determined that the same size is maintained, i.e., growth has stopped.

[0136] By treating cancer according to the methods described herein, the regrowth of tumors can be reduced. In some embodiments, treatment using the methods disclosed herein results in tumor regrowth of at most about 5%, at most about 10%, at most about 20%, at most about 30%, at most about 40%, at most about 50%, or at most about 75%. Tumor regrowth is measured, for example, by measuring the increase in the diameter of the tumor after a previous tumor shrinkage after treatment. Reduction of tumor regrowth is indicated by the tumor not recurring after discontinuation of treatment. A method of treating pain.

[0137] The present disclosure also provides a method of treating or managing pain in a subject in need thereof, the method comprising implanting a biomaterial described herein into a target site of the subject. In some embodiments, the target sites are nerves, connective tissues, and skeletal muscle and tissue. The biomaterial can be filled with an amount of one or more therapeutic agents effective to provide a therapeutically effective amount of one or more drugs to the in situ target site over a period ranging from several weeks to several months, years, as described above. In some embodiments, the subject in need is a human patient in need of treatment of postoperative pain, peripheral nerve injury, or chronic low back pain. In some embodiments, the subject is in need of treatment or management of pain associated with osteoarthritis, diabetic peripheral neuropathy, or musculoskeletal injury or trauma.

[0138] In some embodiments for treating pain described herein, one or more therapeutic agents of the biomaterial are opioids. Non-limiting examples of opioids include morphine, fentanyl, hydromorphone, codeine, oxycodone, hydrocodone, tramadol, methadone, alfentanil, remifentanil, and their derivatives. In some embodiments of the methods for treating pain described herein, one or more therapeutic agents are dexamethasone, ondansetron, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentin, pregabalin, capsaicin, ketamine, memantine, clonidine, dexmedetomidine, tapentadol, transdermal fentanyl, long-acting local anesthetics, cannabinoids, or any combination of the foregoing.

Example

[0139] In some embodiments, the biomaterials (e.g., biomaterial units) disclosed herein are described as "chips". (Example 1) Biomaterial formulation Overview The biomaterial disclosed in this example of the present specification is a 3D printed platform designed to locally deliver drugs to tumor sites. This strategy aimed to avoid clinical side effects caused by the systemic toxicity of chemotherapeutic drugs. The biomaterial is a structured matrix of pores and drug-concentrating regions. The entropy of this drug distribution can provide a very important opportunity to regulate the drug release rate as desired and can be adjusted to deliver therapeutic doses for specific disease indications. The biomaterial may be a combination of a pure polymer and a drug that reduces the possibility of an immune response or crosstalk between various components, for example, without any additives or fillers. The polymer disperses the drug within its matrix and delivers the drug in a slow and sustained manner. The release of the drug is defined by various (e.g., optimized) combinations of the properties of the polymer and the drug. Biomaterials can address unmet needs for novel platform drug delivery technologies. In conventional drug delivery systems, drug particles can diffuse throughout the bloodstream, which reduces the bioavailability of the drug at the target site. Furthermore, with conventional uptake methods, the active ingredient is significantly degraded or the effect is localized. Targeted drug delivery is attracting attention due to the significant need for improving drug delivery efficiency and the need to reduce potential side effects that can occur due to drug accumulation. Targeted drug delivery technology began to accelerate with the emergence of nanotechnology and biocompatible materials. Targeted drug delivery can have a high potential for impact and adoption due to its ability to improve bioavailability and organ specificity. This trend may potentially lead to the adoption of technologies such as organ-specific delivery, cell mimicry, induced delivery, and spatio-temporal control systems. Background This example relates to a pharmaceutical formulation for using a 3D printed polymer structure to locally deliver drugs (e.g., 5-fluorouracil, gemcitabine, etc.) for the treatment of pancreatic cancer. Millions of people worldwide are affected by cancer, and thousands of them die every day. Pancreatic cancer is one of the deadliest cancers with an 85% mortality rate. According to the American Cancer Society, an estimated 60,430 new cases of pancreatic cancer occurred in 2021 alone [Cancer Facts & Figures 2021]. Symptoms appear in the late stages of cancer, by which time the patient's cancer has reached stage 3 or stage 4. The likelihood of survival is very low or zero. The current standard of care treatment is to remove the tumor by a clinical procedure called "pancreaticoduodenectomy" or the Whipple procedure. During the procedure, a portion of the pancreatic head, duodenum, bile duct, and gallbladder are removed to prevent any resection of the tumor. The 5-year survival rate is 27.4% [Improved Survival Following Pancreaticoduodenectomy to Treat Adenocarcinoma of the Pancreas The Influence of Operative Blood Loss]. However, for most patients diagnosed with pancreatic cancer, this surgery is not an option. Chemotherapy is another treatment pathway for pancreatic cancer patients. Chemotherapy is administered either before surgery (neoadjuvant chemotherapy) to reduce the tumor size so that it can be resected, or after surgery (adjuvant chemotherapy) to prevent the growth of any remaining tumor cells or tumor resection. When surgery is not an option, patients are also administered chemotherapy. Antineoplastic drugs, such as 5-fluorouracil, gemcitabine (2’,2’-difluoro-2’-deoxycytidine, dFdC), or gemcitabine hydrochloride, can be administered in an intravenous treatment modality. For example, the standard clinical dosage of gemcitabine is 1 m per patient 2It is 1000 mg per dose and is administered by IV infusion over 30 minutes. This administration is performed weekly for 7 weeks, with a 1-week drug holiday, and can then be administered on days 1, 8, and 15 of a 28-day cycle. Common side effects of this treatment may include nausea, vomiting, rash, fever, elevated liver transaminases, influenza-like symptoms, myelosuppression, pulmonary toxicity, and peripheral edema [Gemcitabine-Induced Pulmonary Toxicity: A Case Report of Pulmonary Veno-Occlusive Disease]. In recent years, chemotherapy regimens including drug combinations such as leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin have been clinically used in the treatment of pancreatic cancer. For chemotherapy regimens, the survival rate is higher compared to surgical procedures and gemcitabine treatment, but severe side effects have been reported including hair loss, redness of the palms and soles, pain or skin peeling, rash, increased risk of sunburn, itching, severe diarrhea, nausea, vomiting, constipation, loss of appetite, weight loss, difficulty swallowing, stomatitis, heartburn, infection (especially when the white blood cell count is low), anemia that may require blood transfusion, bruising, bleeding, headache, fatigue, weakness, dizziness, numbness, tingling, or pain, a "pins and needles" sensation in the hands, feet, arms, and legs, tingling or loss of sensation in the hands, feet, nose, or a feeling of tightness in the throat or jaw, or difficulty swallowing or shortness of breath that may be worsened by exposure to cold, cough, shortness of breath, fever, and pain. Regardless of the type of chemotherapy administered, side effects due to the systemic toxicity of these drugs are very likely to be seen in pancreatic cancer patients. The rapid availability of drugs in the bloodstream may be related to the diffusion throughout most of the body and the action of the drugs on normal cells, but only a small fraction of the drugs reach the cancer cells. The undesirable effects of drugs on healthy cells can be the main cause of some severe side effects in patients. The aim of drug delivery treatment strategies can be to deliver an effective therapeutic dose that is available at the disease site. Therefore, the biomaterials disclosed herein can promote the sustained release of drugs (such as 5-fluorouracil, gemcitabine, etc.) locally at the pancreatic tumor site and can reduce the availability of drugs to healthy cells. The technology disclosed in this specification provides a co - solution to the problems of surgery and chemotherapy and can be provided in parallel with standard - care surgery. The ultra - fine structure achieved by the innovation of constituent materials and 3D printing enables much more stable release over a longer period than previous iterations, thereby obtaining a product prototype capable of achieving the desired effect with a single implantation. The biomaterial provides an alternative to direct surgical resection in delicate areas around the pancreas by localizing the effect of chemotherapy. This is expected to increase the number of patients who can benefit from surgery and, mainly by preventing local recurrence, to increase the overall success rate of surgery. Overall, the sustained and local release characteristics of the biomaterial can enhance the outcomes of both PC surgery and chemotherapy. By reducing the side effects of chemotherapy and the need for in - hospital chemotherapy administration, healthcare costs can also be reduced. Drug delivery treatment strategies include incorporating drugs into polymer structures, which can be nanoparticles, microparticles, or scaffolds with two-dimensional or three-dimensional structures that promote slow, sustained release of small amounts of drugs over long periods. The polymer plays a major role in defining the amount and timing of drug release from the polymer. The US Food and Drug Administration has approved several biodegradable and biocompatible polymers widely used in drug delivery applications, such as polylactide-co-glycolide (PLGA), polycaprolactone (PCL), polyglycolide (PGA), and polylactide (PLA). PCL blended with PLA has been approved by the FDA as a safe food contact agent for packaging purposes. AQLANE Medical BV of the Netherlands manufactures urethral implants under the trade name "Urolon", which is composed of 70% CMC gel and 30% PCL microspheres. PCL is a soft, flexible polymer with a glass transition temperature of -60°C and a melting point of 60°C. However, the melting point of this polymer varies with respect to molecular weight or the number of molecules. The higher the molecular weight, the higher the viscosity. PCL has an average molecular weight of 3000 - 90,000 g / mol. In this study, PCL with molecular weights of 25000, 37000, 50000, and 80000 was used. The molecular weight of PCL plays a very important role in drug release and degradation rates. PCL degrades in two stages, first undergoing hydrolytic cleavage of ester groups and then intracellular degradation of PCl with a molecular weight of less than 3000. PCL degrades rapidly due to bacterial enzymes outside the human body, not inside the human body where bacterial enzymes are not available. Other factors include the geometry of the PCL structure and the microenvironment of the implantation site in the human body. Hydroxyl radicals (OH●) can be a major component of the degradation of PCL in implantable devices. Therefore, it is clear that the molecular weight of PCL plays a major role in defining the drug release profile in delivery devices. Technical strategy Drug release from the polymer can be a very important factor for the biomaterial to provide a therapeutic dose at the tumor site and promote tumor cell death. The release of the drug can be controlled, for example, in two ways. The first is to change the molecular weight of the polymer, thereby affecting the density and permeation characteristics of the PCL. The second is to vary (e.g., optimize) the amount of drug loaded into the polymer. Considering these two factors, the following strategies were planned. Strategy I: To test the effect of the molecular weight of PCL on drug release under uniform drug loading conditions. Strategy II: To test the effect of the molecular weight of PCL on the drug release profile in vitro with different drug loading amounts. By these two strategies, an effective (e.g., optimized) formulation using a suitable polymer that can release the desired amount of drug is found. Strategy 1: Preliminary understanding of the effect of molecular weight on drug release. The size of the polymer (e.g., the number average molar mass of the polymer, e.g., the number average molar mass of PCL) can have an effect on the release profile (e.g., release rate) of drugs (e.g., 5-fluorouracil, gemcitabine, etc.) from the biomaterial containing the polymer, as disclosed herein. For example, the PCL molecular weight may have an effect on the drug release profile in vitro. To evaluate this phenomenon, PCLs with two different number average molar mass values (e.g., 37000 and 50000) were selected and studied using the anticancer drug 5-fluorouracil (5-FU) with an initial loading amount of 20 wt%. A PCL sample with a number average molar mass of about 37000 (i.e., PCL37000, PCL37k, or PCL37) mixed with 20 wt% gemcitabine is referred to as "PG37", and a PCL sample with a number average molar mass of about 50000 (i.e., PCL50000, PCL50k, or PCL50) mixed with 20 wt% gemcitabine is referred to as "PG50". Generally, a PCL sample with a number average molar mass of Z×10 3 is denoted as PCL Z×10 3can be called PCL ZK, or PCL Z.

Table 1

Table 2

Equation

Table 3

Table 4

Table 5

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13 - 1

Table 13 - 2

Table 13-3

Table 14-1

Table 14-2

Table 14-3

Table 14-4

Table 14-5

Table 14-6

Table 14-7

[0140] Embodiment 1. A biomaterial comprising a plurality of geometric elements and a therapeutic agent, wherein a first geometric element of the plurality of geometric elements comprises a first polymer and a therapeutic agent, and at least a part of the first geometric element is porous, a second geometric element of the plurality of geometric elements comprises a second polymer, and at least a part of the second geometric element is substantially non-porous, at least a part of the first geometric element is adjacent to at least a part of the second geometric element, the first polymer or the second polymer has a number average molar mass of more than 6,000 Daltons (Da), optionally, (A) the first polymer and the second polymer have a number average molar mass of more than 6,000 Da, and / or (B) The number average molar mass of the first polymer and the number average molar mass of the second polymer are different, and further, if necessary, a. the number average molar mass of the second polymer is greater than the number average molar mass of the first polymer, and / or b. the number average molar mass of the second polymer is less than the number average molar mass of the first polymer, and / or (C) The number average molar mass of the first polymer is at least or at most about 1 kilodalton (kDa), at least or at most about 2 kDa, at least or at most about 5 kDa, at least or at most about 7 kDa, at least or at most about 10 kDa, at least or at most about 20 kDa, at least or at most about 50 kDa, at least or at most about 70 kDa, at least or at most about 100 kDa, at least or at most about 200 kDa, at least or at most about 500 kDa, at least or at most about 700 kDa, at least or at most about 1,000 kDa, and further, if necessary, a. the number average molar mass of the first polymer is at least about 10 kDa, and / or b. the number average molar mass of the first polymer is at most about 100 kDa, and / or (D) The number average molar mass of the second polymer is at least or at most about 1 kilodalton (kDa), at least or at most about 2 kDa, at least or at most about 5 kDa, at least or at most about 7 kDa, at least or at most about 10 kDa, at least or at most about 20 kDa, at least or at most about 50 kDa, at least or at most about 70 kDa, at least or at most about 100 kDa, at least or at most about 200 kDa, at least or at most about 500 kDa, at least or at most about 700 kDa, at least or at most about 1,000 kDa, and further, if necessary, a. the number average molar mass of the second polymer is at least about 10 kDa, and / or b. the number average molar mass of the second polymer is at most about 100 kDa, and / or (E) The first polymer includes polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA), and optionally, the first polymer includes PCL, and / or (F) The second polymer includes polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA), and optionally, the second polymer includes PCL, and / or (G) The therapeutic agent includes an anticancer agent, an antibacterial agent, an antibiotic, a local anesthetic or analgesic, a statin, and / or an anti-inflammatory agent, and / or (H) The therapeutic agent includes capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, and / or vinorelbine, and optionally, the therapeutic agent includes fluorouracil, Biological material.

[0141] Embodiment 2. A biological material including a plurality of geometric elements and a therapeutic agent, wherein a first geometric element of the plurality of geometric elements includes a first polymer and a therapeutic agent, the amount of the therapeutic agent in the first geometric element is more than 30% based on the weight of the first polymer, and at least a part of the first geometric element is porous, a second geometric element of the plurality of geometric elements is formed by a second polymer, and at least a part of the second geometric element is substantially non-porous, at least a part of the first geometric element is adjacent to at least a part of the second geometric element, optionally, (A) The amount of the therapeutic agent in the first geometric element is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than that, based on the weight of the first polymer. Optionally, the amount of the therapeutic agent in the first geometric element is more than 35% based on the weight of the first polymer, and / or (B) The amount of the therapeutic agent in the first geometric element is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than that, based on the combined weight of the first polymer and the second polymer. Optionally, the amount of the therapeutic agent in the first geometric element is more than 35% based on the combined weight of the first polymer and the second polymer, and / or (C) The first polymer includes polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA). Optionally, the first polymer includes PCL, and / or (D) The second polymer includes polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA). Optionally, the second polymer includes PCL, and / or (E) The therapeutic agent includes an anti-cancer agent, an antibacterial agent, an antibiotic, a local anesthetic or analgesic, a statin, and / or an anti-inflammatory agent, and / or (F) The therapeutic agent includes capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, and / or vinorelbine, Optionally, the therapeutic agent further includes fluorouracil, and / or (G) When the porosity of the first geometric element is confirmed by scanning electron microscopy, thermoporometry and / or cryoporometry, at least or up to about 1%, at least or up to about 2%, at least or up to about 5%, at least or up to about 7%, at least or up to about 10%, at least or up to about 15%, at least or up to about 20%, at least or up to about 25%, at least or up to about 30%, at least or up to about 35%, at least or up to about 40%, at least or up to about 45%, at least or up to about 50%, at least or up to about 55%, at least or up to about 60%, at least or up to about 65%, at least or up to about 70%, at least or up to about 75%, at least or up to about 80%, at least or up to about 85%, at least or up to about 90%, at least or up to about 95%, or at least or up to about 99%, Biological material.

[0142] Embodiment 3. A method of treating a condition of a subject in need thereof, comprising administering to the subject a biological material comprising a plurality of geometric elements and a therapeutic agent, The first geometric element of the plurality of geometric elements includes a first polymer and a therapeutic agent, and at least a part of the first geometric element is porous, The second geometric element of the plurality of geometric elements includes a second polymer, and at least a part of the second geometric element is substantially non-porous, At least a part of the first geometric element is adjacent to at least a part of the second geometric element, The first polymer or the second polymer has a number average molar mass of more than 6,000 Daltons (Da), Optionally, (I) The first polymer and the second polymer have a number average molar mass of more than 6,000 Da, and / or (J) The number average molar mass of the first polymer and the number average molar mass of the second polymer are different, Further optionally, a. The number average molar mass of the second polymer is greater than the number average molar mass of the first polymer, and / or b. The number average molar mass of the second polymer is less than the number average molar mass of the first polymer, and / or (K) The number average molar mass of the first polymer is at least or up to about 1 kilodalton (kDa), at least or up to about 2 kDa, at least or up to about 5 kDa, at least or up to about 7 kDa, at least or up to about 10 kDa, at least or up to about 20 kDa, at least or up to about 50 kDa, at least or up to about 70 kDa, at least or up to about 100 kDa, at least or up to about 200 kDa, at least or up to about 500 kDa, at least or up to about 700 kDa, at least or up to about 1,000 kDa, Further optionally, a. The number average molar mass of the first polymer is at least about 10 kDa, and / or b. The number average molar mass of the first polymer is at most about 100 kDa, and / or (L) The number average molar mass of the second polymer is at least or at most about 1 kilodalton (kDa), at least or at most about 2 kDa, at least or at most about 5 kDa, at least or at most about 7 kDa, at least or at most about 10 kDa, at least or at most about 20 kDa, at least or at most about 50 kDa, at least or at most about 70 kDa, at least or at most about 100 kDa, at least or at most about 200 kDa, at least or at most about 500 kDa, at least or at most about 700 kDa, at least or at most about 1,000 kDa, and optionally, a. the number average molar mass of the second polymer is at least about 10 kDa, and / or b. the number average molar mass of the second polymer is at most about 100 kDa, and / or (M) The first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA), optionally, the first polymer comprises PCL, and / or (N) The second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA), optionally, the second polymer comprises PCL, and / or (O) The therapeutic agent comprises an anti-cancer agent, an antibacterial agent, an antibiotic, a local anesthetic or analgesic, a statin, and / or an anti-inflammatory agent, and / or (P) The therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, and / or vinorelbine, Further optionally, the therapeutic agent comprises fluorouracil, Further optionally, the condition is cancer, and optionally the cancer is solid tumor, colorectal cancer, rectal cancer, anal cancer, lower gastrointestinal cancer, pancreatic cancer, lung cancer, bone cancer, or locally advanced cancer, Further optionally, the administering step comprises implanting a biomaterial adjacent to the tumor in the subject. Method.

[0143] Embodiment 4. A method of treating a condition of a subject in need thereof, comprising administering to the subject a biomaterial comprising a plurality of geometric elements and a therapeutic agent, wherein a first geometric element of the plurality of geometric elements comprises a first polymer and a therapeutic agent, the amount of the therapeutic agent in the first geometric element is more than 30% relative to the weight of the first polymer, and at least a part of the first geometric element is porous, wherein a second geometric element of the plurality of geometric elements is formed by a second polymer, and at least a part of the second geometric element is substantially non-porous, at least a part of the first geometric element is adjacent to at least a part of the second geometric element, Optionally, (H) the amount of the therapeutic agent in the first geometric element is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more relative to the weight of the first polymer, Further optionally, the amount of the therapeutic agent in the first geometric element is more than 35% relative to the weight of the first polymer, and / or (I) the amount of the therapeutic agent in the first geometric element is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more relative to the combined weight of the first polymer and the second polymer, Further optionally, the amount of the therapeutic agent in the first geometric element is more than 35% with respect to the weight of the combination of the first polymer and the second polymer, and / or (J) the first polymer includes polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA), Further optionally, the first polymer includes PCL, and / or (K) the second polymer includes polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), and / or polyethylene glycol diacrylate (PEGDA), Further optionally, the second polymer includes PCL, and / or (L) the therapeutic agent includes an anti-cancer agent, an antibacterial agent, an antibiotic, a local anesthetic or an analgesic, a statin, and / or an anti-inflammatory agent, and / or (M) the therapeutic agent includes capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, and / or vinorelbine, Further optionally, the therapeutic agent includes fluorouracil, and / or (N) When the porosity of the first geometric element is confirmed by scanning electron microscopy, thermoporometry and / or cryoporometry, it is at least or at most about 1%, at least or at most about 2%, at least or at most about 5%, at least or at most about 7%, at least or at most about 10%, at least or at most about 15%, at least or at most about 20%, at least or at most about 25%, at least or at most about 30%, at least or at most about 35%, at least or at most about 40%, at least or at most about 45%, at least or at most about 50%, at least or at most about 55%, at least or at most about 60%, at least or at most about 65%, at least or at most about 70%, at least or at most about 75%, at least or at most about 80%, at least or at most about 85%, at least or at most about 90%, at least or at most about 95%, or at least or at most about 99%, Optionally, the therapeutic agent includes fluorouracil, Optionally, the condition is cancer, and optionally the cancer is solid tumor, colorectal cancer, rectal cancer, anal cancer, lower gastrointestinal cancer, pancreatic cancer, lung cancer, bone cancer, or locally advanced cancer, Optionally, the administering step includes implanting a biomaterial adjacent to the tumor in the subject, Method.

Claims

1. A biomaterial comprising multiple geometric elements and therapeutic agents, (a) The first geometric element of the plurality of geometric elements comprises the first polymer and the therapeutic agent, and at least a portion of the first geometric element is porous. (b) The second geometric element of the plurality of geometric elements comprises a second polymer, and at least a portion of the second geometric element is substantially nonporous, (c) At least a portion of the first geometric element is adjacent to at least a portion of the second geometric element, (d) The first polymer or the second polymer having a number average molar mass greater than 6,000 Daltons (Da), Biomaterials.

2. The biomaterial according to claim 1, wherein the first polymer and the second polymer have a number-average molar mass of more than 6,000 Da.

3. The biomaterial according to claim 1, wherein the number average molar mass of the first polymer and the number average molar mass of the second polymer are different.

4. The biomaterial according to claim 1, wherein the number-average molar mass of the first polymer is at least about 10 kDa.

5. The biomaterial according to claim 1, wherein the number-average molar mass of the first polymer is at most about 100 kDa.

6. The biomaterial according to claim 1, wherein the number-average molar mass of the second polymer is at least about 10 kDa.

7. The biomaterial according to claim 1, wherein the number-average molar mass of the second polymer is at most about 100 kDa.

8. The biomaterial according to claim 1, wherein the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

9. The biomaterial according to claim 1, wherein the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

10. The biomaterial according to claim 1, wherein the therapeutic agent comprises an anticancer agent, an antibacterial agent, an antibiotic, a local anesthetic or analgesic, a statin, and / or an anti-inflammatory agent.

11. The biomaterial according to claim 1, wherein the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, phloxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, larcitrexed, regorafenib, vincristine, or vinorelbine.

12. The biomaterial according to claim 1, wherein the therapeutic agent comprises fluorouracil.

13. A biomaterial comprising multiple geometric elements and therapeutic agents, (a) The first geometric element of the plurality of geometric elements comprises the first polymer and the therapeutic agent, the amount of the therapeutic agent in the first geometric element is greater than 30% of the weight of the first polymer, and at least a portion of the first geometric element is porous. (b) The second geometric element of the plurality of geometric elements is formed of a second polymer, and at least a portion of the second geometric element is substantially nonporous, (c) At least a portion of the first geometric element is adjacent to at least a portion of the second geometric element, Biomaterials.

14. The biomaterial according to claim 13, wherein the amount of the therapeutic agent in the first geometric element is more than 35% of the weight of the first polymer.

15. The biomaterial according to claim 13, wherein the amount of the therapeutic agent in the first geometric element is more than 10% of the weight of the combination of the first polymer and the second polymer.

16. The biomaterial according to claim 13, wherein the amount of the therapeutic agent in the first geometric element is more than 35% of the weight of the combination of the first polymer and the second polymer.

17. The biomaterial according to claim 13, wherein the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

18. The biomaterial according to claim 13, wherein the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

19. The biomaterial according to claim 13, wherein the therapeutic agent comprises an anticancer agent, an antibacterial agent, an antibiotic, a local anesthetic or analgesic, a statin, or an anti-inflammatory agent.

20. The biomaterial according to claim 13, wherein the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, larcitrexed, regorafenib, vincristine, or vinorelbine.

21. The biomaterial according to claim 13, wherein the therapeutic agent comprises fluorouracil.

22. The biomaterial according to claim 13, wherein the porosity of the first geometric element is at least about 1% when confirmed by scanning electron microscopy, thermoporometry and / or cryoporometry.

Images