Drug-eluting surgical articles and methods of use thereof

Abstract

A biological material comprising a first porous polymer, a second non-porous polymer, and a therapeutic agent, and a method of using the same for treating a condition are disclosed. The biomaterials disclosed herein may be, for example, surgical articles. Implanting the biomaterials disclosed herein in a subject can treat, for example, cancer.

Description

[0001] Cross-references

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 342,012 filed on May 13, 2022 and U.S. Provisional Patent Application No. 63 / 342,531 filed on May 16, 2022, each of which is incorporated herein by reference in its entirety.

[0003] Statement Regarding Federally Funded Research

[0004] This invention was made with Government support under Grant No. 7203584328 awarded by the National Science Foundation. The Government has certain rights in this invention. Background Art

[0005] Implantation of biomaterials can allow for targeted delivery of therapeutically effective amounts of therapeutic agents. Targeted delivery of therapeutic agents can improve the efficacy of the agent by increasing exposure of the target tissue to the agent and by reducing systemic toxicity.

[0006] Incorporation by reference

[0007] All publications, patents, and patent applications mentioned in this specification are herein 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

[0008] 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, wherein the first porous boundary comprises a polymer and the therapeutic agent, wherein a second geometric element of the first plurality of geometric elements is formed by a non-porous boundary and a first solid region comprising the polymer, wherein the therapeutic agent cannot diffuse into the second geometric element, wherein the first solid region is adjacent to and within the non-porous boundary, and wherein a portion of the first porous boundary is adjacent to a portion of the non-porous boundary.

[0009] In some embodiments, the present disclosure provides a method of treating a condition, the method comprising: implanting a biomaterial into a subject, wherein the biomaterial comprises 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, wherein the first porous boundary comprises a polymer and the therapeutic agent, wherein a second geometric element of the first plurality of geometric elements is formed by a non-porous boundary and a first solid region comprising the polymer, wherein the therapeutic agent cannot diffuse from the first porous boundary into the second geometric element, wherein the first solid region is adjacent to and within the non-porous boundary, and wherein a portion of the first porous boundary is adjacent to a portion of the non-porous boundary.

[0010] 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, wherein 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, wherein at least a portion of the second geometric element is substantially non-porous; (c) the at least a portion of the first geometric element is adjacent to the 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).

[0011] 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, wherein the amount of the therapeutic agent in the first geometric element is greater than 30% by weight of the first polymer, and wherein at least a portion of the first geometric element is porous; (b) a second geometric element of the plurality of geometric elements is formed from a second polymer, wherein at least a portion of the second geometric element is substantially non-porous; and (c) the at least a portion of the first geometric element is adjacent to the at least a portion of the second geometric element. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1A is a line diagram showing the architecture of an exemplary implementation of a monolayer of the biomaterial of the present disclosure.

[0013] Figure 1B Schematic diagram showing diffusion of a therapeutic agent disclosed herein within an article of manufacture.

[0014] Figure 2A and Figure 2B A line diagram of a biomaterial layer of the present disclosure is shown.

[0015] Figure 3 It shows a three-layer Figure 1A The three-layer biomaterial is a single-layer biomaterial as described in .

[0016] Figure 4A A photograph of an approximately 1×1 cm 3-D printed, PCL-based surgical mesh of the present disclosure is shown.

[0017] Figure 4B A side view is shown, which shows Figure 4A Thickness of 1×1 cm 3D printed surgical mesh.

[0018] Figure 5 Shown is the release profile of 5-fluorouracil (5-FU) from the biomaterial of the present disclosure. Error bars represent the standard deviation of three replicates.

[0019] Figure 6 The percentage degradation of PF50, PF37, P50 and P37 formulations is shown graphically.

[0020] Figure 7 The release profile of 5-FU from the biomaterial is shown.

[0021] Figure 8 Embodiments of biomaterials are shown where darker shading may refer to loading of one or more therapeutic agents (eg, 5-fluorouracil, gemcitabine).

[0022] Fig. 9 It is illustrated that the biomaterials disclosed herein can include multiple moieties (eg, N, S, W, E, etc.) that can contain a drug (eg, 5-fluorouracil, gemcitabine).

[0023] Fig.10 A process flow diagram for manufacturing biomaterials is provided.

[0024] Fig.11 An overview of the long-term stability assessment of biomaterials is given.

[0025] Fig.12 An overview of in-use stability assessments of biomaterials is provided.

[0026] Fig.13 It is a computer-aided design (CAD) image of the biomaterial-5-FU.

[0027] Fig.14 This is a photo of the biological material 5-FU.

[0028] Fig.15 The processes for manufacturing biomaterials are summarized.

[0029] Fig.16 A packaging process for biological materials is provided.

[0030] Fig.17 A flow chart for the manufacturing and quality control of biomaterials is provided. DETAILED DESCRIPTION

[0031] Targeted delivery systems for therapeutic agents can increase the efficacy of therapeutic agents by, for example, increasing exposure of target tissues to the therapeutic agent and by reducing systemic toxicity. Targeted delivery may be desirable in the context of therapies that are highly toxic when administered systemically and / or for prolonged periods of time, such as chemotherapeutic agents and opioids.

[0032] Advances in three-dimensional (3D) printing technology can create new opportunities for producing customized delivery systems that can be adapted for a wide range of uses in the operating room. 3D printing can be advantageous due to the relatively low cost, simplicity, and versatility of 3D printing systems, as well as the ability to enable high-speed production of customized devices.

[0033] Disclosed herein is a biomaterial that can be used as a surgical product and / or a drug delivery system that can release a therapeutic agent directly to a target site over an extended period of time. The biomaterial can include one or more therapeutic agents that are loaded into one or more geometric elements of the product. Biomaterials, such as surgical products, can be suitable for in situ sustained release of one or more therapeutic agents. In some embodiments, surgical products are printed using an extrusion 3D printing method. Biomaterials can be custom printed into shapes and sizes suitable for in situ coverage of target sites. Biomaterials for in situ implantation can be in the general form of surgical tape or mesh, or can be folded and / or layered. Suitable target sites include any site in the body of an object that needs to be treated with one or more therapeutic agents. Non-limiting examples of target sites include tissues such as blood vessels, lymph nodes, cartilage, bone, liver, lungs, heart, pancreas, spleen, gastrointestinal tract, brain, pelvis, breast and lung tissue. In some embodiments, biomaterials can be applied to deep tissues and connective tissues, such as muscle and smooth muscle.

[0034] Biomaterials disclosed herein may include polymeric materials, wherein one or more therapeutic agents may be dispersed in at least a portion of the polymeric material. In some embodiments, the polymeric material may also include one or more additives. The polymeric material may include or consist of one or more bioresorbable and / or biodegradable polymers or a polymer mixture including at least one bioresorbable and / or biodegradable polymer.

[0035] In some embodiments, the 3D printed surgical article is sterile, sterilizable, and / or sterilized prior to implantation in a subject.

[0036] The biomaterials disclosed herein can be biocompatible. Biocompatible biomaterials can be administered or implanted into a subject without causing adverse effects, such as immune and / or inflammatory responses.

[0037] Biomaterials disclosed herein can be biodegradable. Biodegradable biomaterials can be degraded (partially or completely) into non-toxic products under physiological conditions, which can be metabolized or discharged from the body. In some cases, biodegradable materials are degraded by enzymatic activity, such as by enzymatic hydrolysis.

[0038] In some embodiments, the biomaterials of the present disclosure are bioresorbable or bioabsorbable. Bioresorbable or bioabsorbable materials can be broken down and absorbed by cells and / or tissues.

[0039] In some embodiments, the biomaterials described herein are configured to resorb and / or degrade within a time 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 in situ placement. The resorption and / or degradation time can be adjusted by controlling the composition of the polymeric material (including the type of polymer and the porosity of the material) and by two-dimensional and three-dimensional arrangements of geometric elements and including articles.

[0040] Surgical articles as described herein may include one geometric element or multiple geometric elements. In some embodiments, the geometric elements in the multiple geometric elements are in fluid communication with each other. In some embodiments, the multiple geometric elements are printed on the xy plane, for example as a strip, grid or other shape to form a biomaterial of a desired shape and / or size. In some embodiments, the multiple geometric elements can be printed vertically, one above the other. In some embodiments, the thickness of a single layer article may be in the range of 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.

[0041] In some embodiments, the biomaterial of the present disclosure includes multiple layers, wherein each layer includes multiple geometric elements. For example, the biomaterial of the present disclosure may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more layers. In some embodiments, each layer of the biomaterial is oriented so that the layer is offset from the unit above and / or below, for example at a defined 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.

[0042] The overall size of the biomaterial of the present disclosure can be adapted to accommodate 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 biomaterial of the present disclosure can have any shape. For example, the overall shape of a surgical article according to the present specification can be circular, oval, rectangular, triangular, octagonal, pentagonal, hexagonal, heptagonal, or square, and can be sized to cover, for example, about 4 cm 2 To about 200cm 2 In some embodiments, the size of the article is suitable for covering an area of ​​about 20 cm 2 To about 50cm 2 、About 50cm 2 To about 100cm 2 or about 100cm 2 To about 200cm 2 In some embodiments, the size of the article can range from about 2 cm x about 2 cm to about 12 cm x about 10 cm. For example, the biomaterial of the present disclosure can be a square article of 2 cm x 2 cm, 4 cm x 4 cm, 6 cm x 6 cm, or 8 cm x 8 cm, or a rectangular article of 4 cm x 6 cm, 8 cm x 6 cm, 10 cm x 8 cm, or 12 cm x 10 cm.

[0043] In some embodiments, the biomaterials (eg, surgical articles) of the present disclosure may also include loops or similar features configured to facilitate placement of the biomaterial in situ, such as by suturing.

[0044] The biomaterial disclosed herein can have a flexible structure. The biomaterial can be in a dosage form that is locally administered using minimally invasive / endoscopic surgery. The biomaterial can allow 5-FU to directly target tumor cells at difficult-to-reach tumor sites. This site-specific delivery technology is expected to reduce side effects caused by systemic therapy. The biomaterial can shrink local tumors, relieve local symptoms, and potentially prevent or reduce the possibility of life-changing surgeries such as colostomy.

[0045] In some embodiments, biomaterials disclosed herein are radiopaque. In some embodiments, biomaterials disclosed herein do not include or substantially do not include additives or fillers other than drugs disclosed herein and excipients (e.g., PCL). In some embodiments, biomaterials release active pharmaceutical ingredients (API) from the holes in biodegradable polymers in a slow release (e.g., biphasic release) mode over a period of 4 weeks. The release can be enhanced by the hydrophobicity of the product polymer.

[0046] Structure of geometric elements

[0047] The biomaterial of the present disclosure can include multiple geometric elements. The geometric elements in the multiple geometric elements can be adjacent to each other and / or fluidly connected. 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 element can further include one or more therapeutic agents disclosed herein. The boundary forming the geometric element can be porous, non-porous or minimally porous. The porous boundary can allow the therapeutic agent to diffuse through the boundary into the geometric element formed by the boundary or diffuse out of the geometric element formed by the boundary. In some embodiments, the boundary is minimally porous so that the therapeutic agent cannot diffuse through the boundary and enter the geometric element formed by the boundary.

[0048] The geometric element formed by the border may include, for example, empty space or solid areas within the border. The solid areas of the geometric element may be porous, non-porous, or minimally porous. The porous solid areas may allow the therapeutic agent to diffuse into or out of the geometric element through the solid areas. In some embodiments, the solid areas are minimally porous so that the therapeutic agent cannot diffuse through the solid areas and into the geometric element formed by the border.

[0049] The borders and / or solid areas of the geometric elements may have porosity. In some embodiments, the porosity of the borders or solid areas is from about 10% to about 99%. In some embodiments, the porosity of the borders or solid areas 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 20% to about 90%, To about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. In some embodiments, the porosity of the border 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 border 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 border 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%.

[0050] The porosity of the border and / or solid region can vary throughout the biomaterial of the present disclosure. In some embodiments, a porous border surrounds a minimally porous or non-porous solid region. In some embodiments, a minimally porous or non-porous border surrounds a porous solid region. In some embodiments, a non-porous or minimally porous border surrounds a non-porous or minimally porous solid region. In some embodiments, a porous border surrounds a porous solid region.

[0051] Adjacent geometric elements may share an edge, thereby forming part of the boundary forming the geometric element.In some embodiments, adjacent elements each include different edges / borders that are adjacent to and / or in contact with each other.

[0052] The border can form a geometric element of any shape. For example, the border can form a geometric element of a circle, ellipse, triangle, rectangle, pentagon, hexagon, heptagon, octagon or irregular shape. In some embodiments, the border is formed as a geometric element of a pentagon or decagon. The geometric element in a plurality of geometric elements can be the same or different shapes. In some embodiments, biomaterial or its layer can include a plurality of geometric elements that limit two or more hexagons, triangles and rhombuses or parts thereof. In some embodiments, the scope of the edge length of a particular element can be 1.0mm to 10mm, or 1.0mm to 5mm, or 1.0mm to 3mm. It should be understood that, according to the geometry defined by the edge of the element, the edge can have the same or different lengths. In some embodiments, each edge of a geometric element is consistent in length and / or width.

[0053] In some embodiments, biomaterial disclosed herein is composed of multiple layers, and each layer is formed by multiple open and filled geometric elements forming a defined pattern.Multiple geometric elements may include elements with three, four, five or six edges.In some embodiments, the edge of the element can define one or more geometric shapes, which are selected from the parts of triangles, rhombuses, hexagons and any of the aforementioned shapes.In some embodiments, the triangle is an equilateral triangle and the edge of each geometric element has a consistent length.In some embodiments, the length of the edge is about 1 to about 3mm, about 1 to about 2mm, such as about 1.0mm, about 1.5mm, about 2.0mm, about 2.5mm or about 3.0mm.

[0054] One or more therapeutic agents can be loaded into the geometric elements. For example, one or more geometric agents can be dispersed within the solid area or border of one or more geometric elements of the biomaterial of the present disclosure.

[0055] Arrangement of geometric elements

[0056] In some embodiments, a plurality of geometric elements forming a biomaterial or its layer are arranged in a defined pattern of elements including solid areas (i.e., filled elements) and empty spaces (i.e., open elements), which is suitable for in-situ regulation of the release of therapeutic agents from the drug reservoir elements of the unit product. For example, the size and shape of the elements forming the biomaterial or its layer can be increased or decreased to adjust the surface area of ​​the filled elements and the pore size of the open elements, thereby regulating the release of the therapeutic agent from the product. The volume and number of elements loaded with therapeutic agents can determine the amount of therapeutic agents in the unit product and the amount released in situ at the target site. The volume of the element loaded with therapeutic agents can be increased, for example, by printing multiple biomaterial monolayers stacked on top of each other until the desired thickness is reached, thereby allowing a higher loading volume of the therapeutic agent. The defined pattern of open elements and filled geometric elements can also be used to adjust the total surface area of ​​the unit product, as well as the surface area of ​​the unit product from which the therapeutic agent is released.

[0057] Release of therapeutic agents

[0058] In situ release of one or more therapeutic agents from the biomaterials of the present disclosure to a target site may occur from an exposed surface of the biomaterial. Additionally or alternatively, one or more therapeutic agents may diffuse within the biomaterials disclosed herein.

[0059] For example, in some embodiments, a defined pattern of open geometric elements and filled geometric elements with porous and / or non-porous components (e.g., borders or solid areas) can be used to guide or focus any intra-biological diffusion of therapeutic agents to a defined area of ​​the biomaterial. The focused diffusion of therapeutic agents can have the effect of releasing therapeutic agents more concentratedly from an area of ​​the biomaterial. Therefore, depending on the type of therapy, duration of treatment, and location of the in situ target site, the amount and rate of release of therapeutic agents from the biomaterials described herein can be controlled by forming a defined pattern of open geometric elements and filled geometric elements of the biomaterial, comprising one or more additives (such as poragen) and the amount of the medicament loaded into the geometric elements of the biomaterial.

[0060] In some embodiments, the release of therapeutic agents from biomaterials disclosed herein can be regulated by increasing the thickness of the biomaterial (e.g., by using multiple layers) and by isolating geometric elements loaded with therapeutic agents in the inner layer of the folded biomaterial or biomaterial stack or its layer. Folding and stacking the layers of biomaterials in this way can reduce the surface area for releasable therapeutic agents. In some embodiments, surgical products can be formed by alternating layers of unit products in a stacked configuration, wherein the alternating layers are staggered or tilted, for example, at about 180 degrees, about 90 degrees, or about 45 degrees. For example, in a staggered configuration, two or more layers of biomaterials are stacked up and down at 180 degrees, 90 degrees, or 45 degrees and are horizontally layered. In some embodiments, the thickness of the folded or stacked product can be in the range of about 0.5 cm to about 3 cm. In some embodiments, the thickness of the folded or stacked product is about 0.5 cm, about 1.0 cm, about 1.5 cm, or about 2.0 cm.

[0061] In some embodiments, one or more therapeutic agents may be coated onto the surface of a biomaterial in addition to or instead of being dispersed within the polymeric material of the biomaterial.

[0062] Biomaterial structure

[0063] A schematic diagram of a non-limiting example of a biomaterial of the present disclosure is shown in Figure 1A In. Figure 1A As shown, the biomaterial (100) of the present disclosure may include twenty-seven open (i.e., filled with empty space) elements or filled elements defining five different geometric shapes and portions thereof. Two filled triangular elements (101) and seven filled rhombus elements (102) may be positioned to regulate the diffusion of therapeutic agents injected into the biomaterial portion (including in adjacent filled hexagonal elements (103)). In some embodiments, each of the filled elements comprises the same polymer or a mixture of polymers. The filled elements may comprise polymers or mixtures of polymers having the same or different porosities. For example, some filled elements may be used as barriers to the diffusion of the material of the therapeutic agent, while other filled elements may comprise pores that are used to allow the material of the therapeutic agent to diffuse into the region defined by the porous filled element. The porosity of the polymers constituting the biomaterial may be adjusted by the manufacturing process.

[0064] exist Figure 1AIn the embodiment of the present invention, the filled triangular element (101) is formed by a non-porous border (109) surrounding a substantially non-porous solid area. The filled triangular element (109) can be used to focus the material diffusion of the therapeutic agent to adjacent areas defined by porous elements or open elements, such as filled hexagonal elements (103), open hexagonal elements (105) and / or open triangular elements and portions thereof (104). The focusing of the material diffusion can, for example, target the release of the therapeutic agent to a defined area of ​​the biomaterial so that it is released in a more concentrated manner at a specific area within the in situ target site.

[0065] like Figure 1A As shown, the biomaterial disclosed herein may include four filled hexagonal elements (103) formed by a porous boundary (108) and a solid area, each of which includes a polymer and a therapeutic agent dispersed in the polymer. The biomaterial may also include two filled diamond elements (106) formed by a solid area and a porous boundary, each of which includes a polymer and a therapeutic agent dispersed in the polymer. In some embodiments, the porous boundary is formed by the edge of the solid area. Throughout the biomaterial, the boundary of the geometric element with a solid area may have a composition that is the same as or different from the composition of the solid area. In some embodiments, the biomaterial comprises a diamond-shaped filled element (102) formed by a porous boundary and a porous solid area, which is not injected with a therapeutic agent, but allows the material of the therapeutic agent to diffuse into these diamond-shaped filled elements (102). The diffusion of the therapeutic agent into the diamond-shaped element (102) that is not injected with the therapeutic agent increases the surface area from which the therapeutic agent diffuses to the in situ target site.

[0066] The biomaterials disclosed herein may also include a plurality of filled elements and open elements that are used to increase the total surface area of ​​the biomaterial, impart structural integrity to the biomaterial, impart flexibility to the biomaterial, and / or serve as optional fixation points on the biomaterial. Figure 1A As shown, the open elements (104, 105) of the biomaterial disclosed herein can be used as fixing points to sew the biomaterial in place at the target site. The border (107) forming the open elements (104, 105) can be a porous or non-porous border. In some embodiments, the border forming the open elements (104, 105) of the biomaterial disclosed herein includes a polymer and a therapeutic agent (e.g., 5-fluorouracil) injected into the polymer.

[0067] The biomaterial disclosed herein can be one or more layers. For example, the biomaterial of the present disclosure can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more layers. Non-limiting examples of single-layer biomaterials are shown in Figure 2A and Figure 2B middle. Figure 2A A front view is shown, while Figure 2BA rotated view of a single layer article is shown. A non-limiting example of a multilayer biomaterial is shown in Figure 3 middle. Figure 3 Depicted is a layered biomaterial comprising three layers of the biomaterial depicted in FIG. 1 , wherein each layer is offset by approximately 30 degrees.

[0068] Diffusion within the material

[0069] In some embodiments, the biomaterials disclosed herein regulate the diffusion of therapeutic agents within and from the biomaterial. Figure 1A A non-limiting example of a diffusion pattern within a material (the biological material depicted in Figure 1B In. Figure 1A and Figure 1B In the present invention, the filled hexagonal elements (103) and the diamond elements (b) contain a large amount of therapeutic agent per unit of biomaterial, but the edges of the defining elements also contain therapeutic agent. In some embodiments, the six filled hexagonal elements may contain a total of 50-500 mg, 100-400 mg, or 150-250 mg of therapeutic agent. Each element may contain the same or different amounts of therapeutic agent. In some embodiments, the therapeutic agent diffuses into the area defined by the filled diamond elements (102), and the filled diamond elements (102) have a porosity that facilitates such diffusion. In some embodiments, the biomaterial disclosed herein also includes a diamond-shaped filled element (106) infused with a therapeutic agent, which serves as an additional reservoir for the therapeutic agent.

[0070] polymer

[0071] Biomaterials described herein can be formed by 3D printed polymer materials. In some embodiments, the polymer material may include a bioresorbable polymer and / or a biodegradable polymer, or a polymer mixture including one or more bioresorbable polymers and / or biodegradable polymers. Suitable polymers include, but are not limited to, polycaprolactone (PCL), poly(lactic acid) (PLA), poly(lactic acid-co-glycolic acid), also interchangeably referred to as poly(lactide-co-glycolide) (PLGA), poly(ethylene glycol) diacrylate (PEGDA) and poly(esteramide) copolymer (PEA).

[0072] In some embodiments, the polymeric material comprises or consists of PCL. In some embodiments, the polymeric material is a blend of PCL with 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 blended with PCL are selected from polyvinyl chloride and polyethylene oxide (PEO), or are selected from PEA, polyesters, poly(α-hydroxy acids), polylactones, polyorthoesters, polycarbonates, polyanhydrides, polyphosphazenes, or gelatin-based polymers, such as poly(ethylene glycol) (PEG)-gelatin methacrylate.

[0073] In some embodiments, the polymer 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 polymer material includes a 1:1-5:1 mixture of PCL / PLGA, a 1:1-2:1 mixture of PCL / PLGA. The ratio of lactide:glycolide of PLGA can also be changed to adjust the release of the therapeutic agent and the in situ degradation time of the product. 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 (stretched) polymer fibers present in the copolymer. Increasing the number of elongated fibers throughout the polymer product allows more drugs to be released from the product. In some embodiments, the PLGA% weight ratio is 50:50-90:10 lactide / glycolide. In some embodiments, the PLGA% weight ratio is 85:15 lactide / glycolide, 60:40 lactide / glycolide.

[0074] Regulation of the density and / or porosity of the polymeric material can regulate the release of the therapeutic agent from the biomaterial. 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 of the polymeric material. In some embodiments, the polymeric material comprises or is composed of PCL, and PCL has micropores with a size in the range of 50-250 microns, wherein the average size is about 80 microns. Blending PCL with another polymer (such as PLA, PLGA, PEGDA or PEO) will produce larger pores, for example in the range of 200 to 800 microns. In some embodiments, less porous polymeric materials can be used to slow the release of the therapeutic agent. For example, a polymeric material comprising about 60% to 100% PCL, or 60-80% PCL, or 80-100% PCL can be used.

[0075] In some embodiments, the biomaterial of the present disclosure may include geometric elements, each of which includes two or more different polymer materials. For example, the polymer material forming the edge of the element may be different from the polymer material forming the "filler" of the filling element, and different filling elements may be filled with different polymer materials. The polymer material may be different, for example, in the type of polymer or polymer mixture constituting the polymer material. In addition, the polymer materials forming different parts of the geometric element may have different densities and / or porosities, and may also be different in the optional additives they contain. For example, a multi-head 3D printer may allow different substances to be printed simultaneously. For example, each head may contain different ingredients, so one head may contain a selected polymer and a therapeutic agent, while the second head may only contain a polymer. When the STL file is converted to G code, a programmable code for the multi-head printer is created to allow the 3D printer to read which product fragments contain PCL, and which product fragments contain PCL and drugs (as shown in the programming). Similarly, more than one drug can be printed at a time. For example, an analgesic (e.g., NSAID) can be printed simultaneously with a chemotherapeutic (e.g., 5-fluorouracil).

[0076] In some embodiments, the biomaterial includes a polymer (e.g., a first polymer and / or a 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.

[0077] In some embodiments, the biomaterial includes a polymer (e.g., a first polymer and / or a second polymer disclosed herein), and the polymer has a number average molar mass of at most 1 kilodalton (kDa), at most 2 kDa, at most 5 kDa, at most 7 kDa, at most 10 kDa, at most 20 kDa, at most 30 kDa, at most 40 kDa, at most 50 kDa, at most 70 kDa, at most 100 kDa, at most 200 kDa, at most 500 kDa, at most 700 kDa, or at most 1,000 kDa.

[0078] In some embodiments, the biomaterial includes a polymer (e.g., a first polymer and / or a 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.

[0079] In some embodiments, the biomaterial includes 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 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.

[0080] In some embodiments, the biomaterial includes a first polymer and a second polymer, and the first polymer and the second polymer each have a number average molar mass of at most 1 kiloDalton (kDa), at most 2 kDa, at most 5 kDa, at most 7 kDa, at most 10 kDa, at most 20 kDa, at most 30 kDa, at most 40 kDa, at most 50 kDa, at most 70 kDa, at most 100 kDa, at most 200 kDa, at most 500 kDa, at most 700 kDa, or at most 1,000 kDa.

[0081] In some embodiments, the biomaterial includes 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.

[0082] additive

[0083] In some embodiments, the biomaterial of the present disclosure or a portion thereof may include one or more additives. Non-limiting examples of additives include radiopaque agents, colorants, oils (eg, silicones), and porogens.

[0084] The density and / or porosity of the polymeric material, and therefore the release of the therapeutic agent 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 includes a porogen. The term "porogen" refers to a material that diffuses, dissolves, and / or degrades to leave pores within the polymeric material. In some embodiments, a 3D printed surgical article as described herein can be printed with at least a portion of a polymeric material that includes a porogen. Depending on the porogen used, the porogen can then diffuse, dissolve, and / or degrade before or after implantation, thereby 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 glass; silicate nanoparticles such as Laponite; TM ); and water-soluble or physiologically unstable natural or synthetic polymers including, for example, poly(vinyl pyrrolidone), pullulan, poly(glycolide), poly(lactide), poly(lactide-co-glycolide), other polyesters, and starch.

[0085] In some embodiments, the porogen of the present disclosure is a bioactive glass, such as a ceramic in the Na-Ca-Si-PO system. In embodiments, the bioactive glass includes SiO2 and CaO. In embodiments, the bioactive glass also includes Na2O and P2O5. In some embodiments, the bioactive glass is selected from Bioactive glass 45S5 (45wt% SiO2, 24.5wt% CaO, 24.5wt% Na2O and 6.0wt% P2O5); bioactive glass 58S, 60wt% SiO2, 36wt% CaO and 4wt% P2O5; bioactive glass 70S30C, 70wt% SiO2 and 30wt% CaO; bioactive glass S53P4, 53wt% SiO2, 23wt% Na2O, 20wt% CaO and 4wt% P2O5 (antibacterial) and hectorite (Na + 0.7 (Si8Mg 5.5 Li 0.3 ) 20 (OH)4] - .

[0086] In some embodiments, sacrificial or fugitive inks may be used to introduce pores or channels into a polymeric material. Non-limiting examples of materials that may be used as fugitive inks include poloxamers, such as Pluronic TM F127, which is composed of hydrophobic poly(propylene oxide) (PPO) and hydrophilic poly(ethylene oxide) (PEO) segments arranged in a PEO-PPO-PEO configuration.

[0087] Therapeutic agents

[0088] Biomaterials described herein may include one or more therapeutic agents in a therapeutically effective amount. In some embodiments, the therapeutic agent is loaded into the solid region of the geometric elements of the biomaterial. In some embodiments, the therapeutic agent may be contained within the boundary (e.g., porous boundary) of the edge of one or more geometric elements forming the article.

[0089] In some embodiments, the one or more therapeutic agents may be selected from anticancer agents, antimicrobial agents, antibiotics, local anesthetics or analgesics, statins, and anti-inflammatory agents.

[0090] In some embodiments, the anticancer agent is selected from capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, vinorelbine, and combinations thereof.

[0091] In some embodiments, antimicrobial agent is an antibiotic. In some embodiments, antibiotic can be a broad-spectrum antibiotic, such as gentamicin, clindamycin and erythromycin, or gram-positive and gram-negative family antibiotics, such as ampicillin and cephalosporin. Non-limiting examples of antibiotics suitable for use herein include penicillin V potassium, cloxacillin sodium, dicloxacillin sodium, oxacillin sodium, carboxyindoline penicillin sodium, oxytetracycline, hydrochloride, tetracycline hydrochloride, clindamycin phosphate, clindamycin, hydrochloride, clindamycin palmitate HCL, lincomycin HCL, neomycin sodium, nitrofurantoin sodium and metronidazole hydrochloride.

[0092] In some embodiments, the therapeutic agent is a local anesthetic or analgesic. Non-limiting examples of local anesthetics or analgesics include lidocaine, bupivacaine, tetracaine, ropivacaine, benzocaine and fentanyl, codeine hydrochloride, codeine phosphate, codeine sulfate, dextromorphamide tartrate, hydrocodone tartrate, hydromorphone hydrochloride, pethidine hydrochloride, methadone hydrochloride, morphine sulfate, morphine acetate, morphine lactate, morphine meconate, morphine nitrate, dihydromorphine phosphate, morphine tartrate, morphine valerate, morphine hydrobromide, morphine hydrochloride and propoxyphene hydrochloride.

[0093] In some embodiments, the therapeutic agent is an anti-inflammatory agent. The anti-inflammatory agent can be selected from non-steroidal anti-inflammatory agents. The 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 embodiments, 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.

[0094] In some embodiments, the therapeutic agent is an anticancer agent. In some embodiments, the anticancer agent is selected from agents used to treat colorectal cancer. In some embodiments, the anticancer agent is selected from gemcitabine (Gemzar TM ), Tomudex TM ), Oxaliplatin (Eloxatin TM ), regorafenib, irinotecan (Camptostar TM ) and 5-fluorouracil (Adrucil TM ) and combinations thereof. In some embodiments, the anticancer agent is selected from capecitabine, fluorouracil, irinotecan and oxaliplatin, and combinations thereof.

[0095] In some embodiments, the anticancer agent is selected from the group consisting of agents used to treat pancreatic cancer. In some embodiments, the anticancer agent is selected from the group consisting of gemcitabine (Gemzar TM ), fluorouracil (5-FU), irinotecan (Camptosar TM ), Oxaliplatin (Eloxatin TM ), Taxol TM or Abraxane TM ), capecitabine (Xeloda TM )), cisplatin, docetaxel (Taxotere TM ) and irinotecan (Onivyde TM ) and their combinations.

[0096] In some embodiments, the anticancer agent is selected from agents used to treat lung cancer. In some embodiments, the anticancer agent is selected from cisplatin (Platinol TM ), Carboplatin TM ), docetaxel TM ), Gemzar TM ), Taxol TM etc.), Navelbine TM etc.), pemetrexed (Alimta TM ) and their combinations.

[0097] In some embodiments, the anticancer agent is selected from agents used to treat bone cancer. In some embodiments, the anticancer agent is selected from adriamycin Cisplatin, etoposide (VP-16), ifosfamide Cyclophosphamide Methotrexate and vincristine and combinations thereof.

[0098] In some embodiments, the therapeutic agent is a cell (eg, a human cell). For example, the one or more therapeutic agents of the biomaterial can be selected from pluripotent stem cells, multipotent stem cells, and induced pluripotent stem cells (iPSCs).

[0099] In some embodiments, the biomaterial includes a geometric element (e.g., a first geometric element or a second geometric element disclosed herein), a polymer (e.g., a first polymer or a second polymer disclosed herein), 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% by weight of the biomaterial, geometric element, or polymer.

[0100] In some embodiments, the biomaterial includes a geometric element (e.g., a first geometric element or a second geometric element disclosed herein), a polymer (e.g., a first polymer or a second polymer disclosed herein), 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% by weight of the biomaterial, geometric element, or polymer.

[0101] In some embodiments, the biomaterial includes a geometric element (e.g., a first geometric element or a second geometric element disclosed herein), a polymer (e.g., a first polymer or a second polymer 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% by weight of the biomaterial, geometric element, or polymer.

[0102] In some embodiments, the biomaterial includes a geometric element (e.g., a first geometric element or a 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, the geometric element, or the 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% by weight of the combination of the first polymer and the second polymer.

[0103] In some embodiments, the biomaterial includes a geometric element (e.g., a first geometric element or a 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, the geometric element, or the 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% by weight of the combination of the first polymer and the second polymer.

[0104] In some embodiments, the biomaterial includes a geometric element (e.g., a first geometric element or a 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, the geometric element, or the 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% by weight of the combination of the first polymer and the second polymer.

[0105] Methods for printing biomaterials

[0106] Also disclosed herein are methods for printing the biomaterials of the present disclosure. In some embodiments, the biomaterial is printed using an extrusion-based process. Extrusion-based 3D printing may include any of: fused filament fabrication (FFF), fused deposition modeling (FDM), stereolithography, and gel media methods (with or without particles).

[0107] The printing of biomaterials may include heating a polymer material to the melting point of the polymer and combining the polymer with a therapeutic agent with or without additional ingredients (such as porogens) to form a suspension of the therapeutic agent in the polymer material. The resulting composition, referred to herein as a "slurry," can then be loaded into a 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 a polymer material with a therapeutic agent and then heating the composition to the melting point of the polymer material to form a slurry. Other ingredients, such as porogens, can be added at any time during the process. The slurry is extruded onto a substrate along a pre-designed path using a layer-by-layer process to form a biomaterial as described herein. In some embodiments, the model of the biomaterial is obtained by computer-aided design (CAD).

[0108] In some embodiments, the biomaterial of the present disclosure includes multiple layers. Each layer can have different geometric structures (e.g., staggered, tilted). Layered biomaterials can be constructed using a layer-by-layer process to achieve an overall grid size of, for example, about 4×about 6 cm×about 0.5 cm (h×w×d).

[0109] In some embodiments, the biomaterial articles described herein are printed in layers using alternating layers of polymeric materials with and without one or more therapeutic agents dispersed in the polymer. For example, (i) a first layer of polymeric material containing a therapeutic agent dispersed in a polymer, (ii) a second layer of polymeric material without a therapeutic agent, the second layer being disposed on the first layer, and (iii) a third layer of polymeric material containing a therapeutic agent dispersed in a polymer, the third layer being disposed on the second layer. The layers are printed in this order, repeated until the article reaches the desired thickness. In some implementations, the article may have a thickness in the range of 0.5 to 3.0 cm, or 0.5 to 2.0 cm, or 0.5 to 1.0 cm.

[0110] Bioprinting parameters

[0111] The methods disclosed herein can utilize needles in a bioprinting process. In some embodiments, one or more polymeric materials, fugitive inks, ECM materials, cell suspensions, or combinations thereof are deposited onto a substrate through a needle. The methods of the present disclosure can print from more than one needle, 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 a diameter expressed using the Birmingham gauge system. In some embodiments, the needle has a diameter of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 22s, 23, 24, 25, 26, 26s, 27, 28, 29, 30, 31, 32, 33, or 34.

[0112] In some embodiments, the diameter of the needle of the present disclosure is between 0.1 mm and 400 mm. In some embodiments, the diameter of the needle of the present disclosure is 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 0.5mm to 40mm, 0.5mm to 50mm, 0.5mm to 100mm, 0.5mm to 200mm, 0.5mm to 300mm, 0.5mm to 400mm, 1mm to 10mm, 1mm to 20mm, 1mm to 30mm, 1mm to 40mm, 1mm to 50mm, 1mm to 100mm, 1mm to 200mm, 1mm to 300mm, 1mm to 400mm, 10mm to 20mm, 10mm to 30mm, 10mm to 40 mm, between 10mm and 50mm, between 10mm and 100mm, between 10mm and 200mm, between 10mm and 300mm, between 10mm and 400mm, between 20mm and 30mm, between 20mm and 40mm, between 20mm and 50mm, between 20mm and 100mm, between 20mm and 200mm, between 20mm and 300mm, between 20mm and 400mm, between 30mm and 40mm, between 30mm and 50mm, between 30mm and 100mm, between 30mm and 200mm, between 30mm and 300mm m, between 30mm and 400mm, between 40mm and 50mm, between 40mm and 100mm, between 40mm and 200mm, between 40mm and 300mm, between 40mm and 400mm, between 50mm and 100mm, between 50mm and 200mm, between 50mm and 300mm, between 50mm and 400mm, between 100mm and 200mm, between 100mm and 300mm, between 100mm and 400mm, between 200mm and 300mm, between 200mm and 400mm or between 300mm and 400mm.In some embodiments, the diameter of the needle of the present disclosure is 0.1mm, 0.2mm, 0.5mm, 1mm, 10mm, 20mm, 30mm, 40mm, 50mm, 100mm, 200mm, 300mm or 400mm. In some embodiments, the diameter of the needle of the present disclosure is at least 0.1mm, at least 0.5mm, at least 1mm, at least 10mm, at least 20mm, at least 30mm, at least 40mm, at least 50mm, at least 100mm, at least 200mm or at least 300mm. In some embodiments, the diameter of the needle of the present disclosure is at most 0.5mm, at most 1mm, at most 10mm, at most 20mm, at most 30mm, at most 40mm, at most 50mm, at most 100mm, at most 200mm, at most 300mm or at most 400mm.

[0113] Method disclosed herein may include using an extruder to pass material through a needle and arrive on a substrate. In some embodiments, a plurality of extruders deposit one or more materials onto a substrate. For example, a 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, print with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more extruders.

[0114] The temperature at which the extruder operates can be controlled. In some embodiments, the extruder is operated at a temperature of about 25°C to about 200°C. In some embodiments, the extruder is operated 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 In some embodiments, the extruder is operated 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., 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 is operated 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 is operated 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 is operated 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.

[0115] In some embodiments, pressurized air is used to move the material through the 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 is operated at a 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 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 is operated at a gas 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 is operated at a gas 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 is operated at a gas pressure of at most about 625 kPa, at most about 650 kPa, at most about 675 kPa, at most about 700 kPa, at most about 725 kPa, at most about 750 kPa, at most about 775 kPa, or at most about 800 kPa.

[0116] In some embodiments, the extruder is operated at a gas pressure of about 60 pounds per square inch (psi) to about 120 psi. In some embodiments, the extruder is operated at 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 116 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 In some embodiments, the extruder is operated at a gas 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, about 108.8 psi, about 112.4 psi, about 116 psi, or about 120 psi. In some embodiments, the extruder is operated at a gas 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 is operated at a gas pressure of at most about 90.6 psi, at most about 94.3 psi, at most about 97.9 psi, at most about 101.5 psi, at most about 105.2 psi, at most about 108.8 psi, at most about 112.4 psi, at most about 116 psi, or at most about 120 psi.

[0117] The methods of the present disclosure may include printing materials at various linear extrusion speeds. In some embodiments, the material is deposited at a linear extrusion speed of about 8 mm / s to about 800 mm / s. In some embodiments, the material is deposited at a linear extrusion speed of about 100 mm / s to about 150 mm / s, about 100 mm / s to about 200 mm / s, about 100 mm / s to about 250 mm / s, about 100 mm / s to about 300 mm / s, about 100 mm / s to about 350 mm / s, about 100 mm / s to about 400 mm / s, about 100 mm / s to about 450 mm / s, about 100 mm / s to about 500 mm / s, about 100 mm / s to about 600 mm / s, about 100 mm / s to about 700 mm / s, about 100 mm / s to about 800 mm / s, about 150 mm / s to about 200 mm / s, about 150 mm / s to about mm / s to about 250 mm / s, about 150 mm / s to about 300 mm / s, about 150 mm / s to about 350 mm / s, about 150 mm / s to about 400 mm / s, about 150 mm / s to about 450 mm / s, about 150 mm / s to about 500 mm / s, about 150 mm / s to about 600 mm / s, about 150 mm / s to about 700 mm / s, about 150 mm / s to about 800 mm / s, about 200 mm / s to about 250 mm / s, about 200 mm / s to about 300 mm / s, about 200 mm / s to about 350 mm / s, about 200 mm / s to about 400 mm / s, about 20 0mm / s to about 450mm / s, about 200mm / s to about 500mm / s, about 200mm / s to about 600mm / s, about 200mm / s to about 700mm / s, about 200mm / s to about 800mm / s, about 250mm / s to about 300mm / s, about 250mm / s to about 350mm / s, about 250mm / s to about 400mm / s, about 250mm / s to about 450mm / s, about 250mm / s to about 500mm / s, about 250mm / s to about 600mm / s, about 250mm / s to about 700mm / s, about 250mm / s to about 800mm / s, about 300mm / s to about 350mm / s, about 300mm / s to about 400mm / s, about 300mm / s to about 450mm / s, about 300mm / s to about 500mm / s, about 300mm / s to about 600mm / s, about 300mm / s to about 700mm / s, about 300mm / s to about 800mm / s, about 350mm / s to about 400mm / s, about 350mm / s to about 450mm / s, about 350mm / s to about 500mm / s, about 350mm / s to about 600mm / s, about 350mm / s to about 700mm / s, about 350mm / s to about 800mm / s,The linear extrusion speed is deposited at about 400 mm / s to about 450 mm / s, about 400 mm / s to about 500 mm / s, about 400 mm / s to about 600 mm / s, about 400 mm / s to about 700 mm / s, about 400 mm / s to about 800 mm / s, about 450 mm / s to about 500 mm / s, about 450 mm / s to about 600 mm / s, about 450 mm / s to about 700 mm / s, about 450 mm / s to about 800 mm / s, about 500 mm / s to about 600 mm / s, about 500 mm / s to about 700 mm / s, about 500 mm / s to about 800 mm / s, about 600 mm / s to about 700 mm / s, about 600 mm / s to about 800 mm / s, or about 700 mm / s to about 800 mm / s. In some embodiments, the material is deposited at a linear extrusion speed of about 8 mm / s, about 10 mm / s, about 100 mm / s, about 150 mm / s, about 200 mm / s, about 250 mm / s, about 300 mm / s, about 350 mm / s, about 400 mm / s, about 450 mm / s, about 500 mm / s, about 600 mm / s, about 700 mm / s, or about 800 mm / s. In some embodiments, the material is deposited at a linear extrusion speed of at least about 8 mm / s, at least about 100 mm / s, at least about 150 mm / s, at least about 200 mm / s, at least about 250 mm / s, at least about 300 mm / s, at least about 350 mm / s, at least about 400 mm / s, at least about 450 mm / s, at least about 500 mm / s, at least about 600 mm / s, or at least about 700 mm / s. In some embodiments, the material is deposited at a linear extrusion speed of at most about 150 mm / s, at most about 200 mm / s, at most about 250 mm / s, at most about 300 mm / s, at most about 350 mm / s, at most about 400 mm / s, at most about 450 mm / s, at most about 500 mm / s, at most about 600 mm / s, at most about 700 mm / s, or at most about 800 mm / s.

[0118] The methods of the present disclosure may include printing material at various volumetric rates. In some embodiments, printing is performed at a volumetric rate of about 1 μL / s to about 100 μL / s. In some embodiments, the flow rate is from about 1 μL / s to about 5 μL / s, from about 1 μL / s to about 10 μL / s, from about 1 μL / s to about 15 μL / s, from about 1 μL / s to about 20 μL / s, from about 1 μL / s to about 25 μL / s, from about 1 μL / s to about 50 μL / s, from about 1 μL / s to about 100 μL / s, from about 5 μL / s to about 10 μL / s, from about 5 μL / s to about 15 μL / s, from about 5 μL / s to about 20 μL / s, from about 5 μL / s to about 25 μL / s, from about 5 μL / s to about 50 μL / s, from about 5 μL / s to about 100 μL / s, from about 10 μL / s to about 15 μL / s, from about 10 μL / s to about Printing is performed at a volumetric speed of about 20 μL / s, about 10 μL / s to about 25 μL / s, about 10 μL / s to about 50 μL / s, about 10 μL / s to about 100 μL / s, about 15 μL / s to about 20 μL / s, about 15 μL / s to about 25 μL / s, about 15 μL / s to about 50 μL / s, about 15 μL / s to about 100 μL / s, about 20 μL / s to about 25 μL / s, about 20 μL / s to about 50 μL / s, about 20 μL / s to about 100 μL / s, about 25 μL / s to about 50 μL / s, about 25 μL / s to about 100 μL / s, or about 50 μL / s to about 100 μL / s. In some embodiments, printing is performed at a volumetric speed of about 1 μL / s, about 5 μL / s, about 10 μL / s, about 15 μL / s, about 20 μL / s, about 25 μL / s, about 50 μL / s, or about 100 μL / s. In some embodiments, printing is performed at a volumetric speed of at least about 1 μL / s, at least about 5 μL / s, at least about 10 μL / s, at least about 15 μL / s, at least about 20 μL / s, at least about 25 μL / s, or at least about 50 μL / s. In some embodiments, printing is performed at a volumetric speed of at most about 5 μL / s, at most about 10 μL / s, at most about 15 μL / s, at most about 20 μL / s, at most about 25 μL / s, at most about 50 μL / s, or at most about 100 μL / s.

[0119] The methods of the present disclosure may include controlling the deposition of materials (e.g., polymers) at a certain resolution. In some embodiments, the methods disclosed herein may control the deposition of materials at a resolution of about 0.01 mm to about 1 mm. In some embodiments, the methods disclosed herein may control the deposition of materials at a resolution of about 0.01 mm to about 0.05 mm, about 0.01 mm to about 0.1 mm, about 0.01 mm to about 0.2 mm, about 0.01 mm to about 0.3 mm, about 0.01 mm to about 0.4 mm, about 0.01 mm to about 0.5 mm, about 0.01 mm to about 1 mm, about 0.05 mm to about 0.1 mm, about 0.05 mm to about 0.2 mm, about 0.05 mm to about 0.3 mm, about 0.05 mm to about 0.4 mm, about 0.05 mm to about 0.5 mm, about 0.05 mm to about 1 mm , about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.3 mm, about 0.1 mm to about 0.4 mm, about 0.1 mm to about 0.5 mm, about 0.1 mm to about 1 mm, about 0.2 mm to about 0.3 mm, about 0.2 mm to about 0.4 mm, about 0.2 mm to about 0.5 mm, about 0.2 mm to about 1 mm, about 0.3 mm to about 0.4 mm, about 0.3 mm to about 0.5 mm, about 0.3 mm to about 1 mm, about 0.4 mm to about 0.5 mm, about 0.4 mm to about 1 mm, or about 0.5 mm to about 1 mm. In some embodiments, the methods disclosed herein can control the deposition of materials with 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 control material deposition 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 control material deposition at a resolution of at most about 0.05 mm, at most about 0.1 mm, at most about 0.2 mm, at most about 0.3 mm, at most about 0.4 mm, at most about 0.5 mm, or at most about 1 mm.

[0120] Computer Systems

[0121] Bioprinting parameters such as deposition rate, extruder pressure, extruder temperature, extruder deposition mode, deposition position, layer thickness, and deposited material can be controlled by a computer system. In some embodiments, the computer system includes a processor, a storage device, an operating system, and a software module 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 other embodiments, the computer system includes an operating system configured to execute executable instructions. In some embodiments, an operating system is software including programs and data that manages the hardware of the device and provides services for executing application programs. As non-limiting examples, suitable server operating systems include FreeBSD, OpenBSD, Linux, MacOS X Windows and By way of non-limiting example, suitable personal computer operating systems include Mac OS and UNIX-like operating systems such as 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 OS, Research In BlackBerry Google Windows OS, Windows OS, Linux, and 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 for temporarily or permanently storing data or programs. In some embodiments, the device is a volatile memory and requires power to maintain the stored information. In some embodiments, the device is a non-volatile memory and retains the stored information when the digital processing device is not powered on. In other embodiments, the non-volatile memory includes flash memory. In some embodiments, the non-volatile memory includes a dynamic random access memory (DRAM). In some embodiments, the non-volatile memory includes a ferroelectric random access memory (FRAM). In some embodiments, the non-volatile memory includes a phase change random access memory (PRAM). In some embodiments, the device is a storage device, which includes, as a non-limiting example, CD-ROM, DVD, flash memory device, disk drive, tape drive, optical drive and cloud computing-based storage. In some embodiments, the storage and / or memory device is a combination of devices such as those disclosed herein.

[0122] In some embodiments, the computer system described herein includes a user interface. In other embodiments, the user interface includes a graphical user interface (GUI), such as a Repetier-Host graphical user interface. In some embodiments, the user interface is interactive, and menus and options are presented to the user for interacting with the computer system and delivery system herein. In some embodiments, the computer system includes a display screen to send 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 other 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 a 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, which is a touch screen or a multi-touch screen. In some embodiments, the input device is a microphone to capture voice or other sound input. In some embodiments, the system and software module disclosed herein are based on an intranet. In some embodiments, the system and software module are based on the Internet. In some embodiments, the computer system and software module are based on the World Wide Web. In some embodiments, the computer system and software module are based on cloud computing. In some embodiments, the computer system and software module are based on data storage devices, as non-limiting examples, including CD-ROM, DVD, flash memory devices, RAM (e.g., DRAM, SRAM, etc.), ROM (e.g., PROM, EPROM, EEPROM, etc.), tape drives, disk drives, optical disk drives, magneto-optical drives, solid-state drives and combinations thereof.

[0123] How to use

[0124] Biomaterials described herein can provide controlled and extended release of one or more therapeutic agents at a target site in situ in a subject's body that needs to treat a disease, disorder or condition that can be treated by one or more therapeutic agents. The release of one or more therapeutic agents from an implanted article can occur by a variety of mechanisms, including but not limited to diffusion through a polymer material, transport through holes or channels filled with fluid in a polymer material, and degradation of the polymer material.

[0125] A plurality of structural features of the biomaterials disclosed herein may be suitable for altering the release of therapeutic agents 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 substructure of the unit biomaterial formed by a defined pattern of geometric elements (e.g., in a layered biomaterial), including the size, shape, and number and arrangement of filled and open geometric elements.

[0126] The macroscopic three-dimensional structure of the biomaterial of the present disclosure may also be suitable for changing the release of the therapeutic agent and / or focusing the release to a specific part or area of ​​the product. For example, the biomaterial can be folded or rolled up to insert into a target site. Multiple unit biomaterials can also be formed or printed into stacked layers with a desired orientation, including a staggered configuration. In some embodiments, the product can be coated with a coating. In some embodiments, the coating prevents sudden 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 medical research and drug development. Dip coating of the product can be achieved by immersing the biomaterial in a polymer-drug solution and then drying the biomaterial to form a thin and uniform coating. Alternatively, a spray method can be used to coat the biomaterial, which allows droplets of the therapeutic agent to be sprayed directly onto the biomaterial itself. In some embodiments, the above combination can be used to coat the biomaterial using a hybrid method.

[0127] 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.

[0128] 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.

[0129] In some embodiments, a therapeutically effective amount of one or more therapeutic agents may be delivered to an in situ target site over a period of time by implanting a biomaterial of the present disclosure.

[0130] The methods disclosed herein can treat a condition by, for example, alleviating, reducing, or reducing the likelihood of one or more symptoms or complications of a disease or condition. In some embodiments, the methods disclosed herein reduce the likelihood of a disease or condition occurring in a subject. For example, in the case of cancer, treating the cancer can include slowing the growth of the cancer, slowing or preventing the occurrence of metastasis or further metastasis, and promoting regression of one or more tumors in the subject being treated.

[0131] In some embodiments, the biomaterial is used to release the drug over a period of, for example, about 3 weeks, about 4 weeks, about 30 days, or about 5 weeks. During this period, a certain amount of drug, 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, approximately 75% of a 20 mg dose of 5-FU can be released to deliver a therapeutic dose of 15 mg.

[0132] 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 three 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 four 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 period of five weeks. 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 period of 30 days.

[0133] 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 three week period. 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 four week period. 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 five 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.

[0134] In some embodiments, a single dose is used. For example, one or more biomaterials are used, and for example, are optionally removed four weeks after implantation. In some embodiments, repeated doses are used. For example, one or more biomaterials are used, and are optionally removed (for example, four weeks after implantation), and then one or more biomaterials are used for the second time (for example, about 30 days after the first dose). In some embodiments, for example, about every four weeks (for example, + / -5 days), about every 30 days (for example, + / -5 days), about every 45 days (for example, + / -5 days) or about every 60 days (for example, + / -5 days), repeated doses are used.

[0135] In some embodiments, the biomaterial includes a dose of a drug disclosed herein (e.g., an active pharmaceutical ingredient (API), such as 5-FU) 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. In some embodiments, the biomaterial includes a dose of a drug 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 includes a dose of a drug, which is 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 includes a dose of a drug, which is at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 40 mg, at most about 60 mg, at most about 80 mg, at most about 100 mg, at most about 120 mg, at most about 140 mg, at most about 160 mg or at most about 180 mg. In some embodiments, the biomaterial includes a dose in a biomaterial unit (e.g., chip) disclosed herein. In some embodiments, the dose is divided between two, three, four or five biomaterial units (eg, chips). The multiple units may be separate, or may be joined (eg, sutured) together.

[0136] Biomaterials disclosed herein can limit systemic exposure to therapeutic agents (e.g., drugs). In some embodiments, the level of the drug in the circulation (e.g., blood or plasma) of a subject to which the biomaterial is topically applied 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 which the therapeutic agent is applied by a systemic route (e.g., intravenously). Biomaterials disclosed herein can limit systemic exposure to therapeutic agents (e.g., drugs). In some embodiments, the level of the drug in the circulation (e.g., blood or plasma) of a subject to which the biomaterial is topically applied 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 which the therapeutic agent is topically applied.

[0137] Methods for treating cancer

[0138] The present disclosure provides a method for 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 a portion of an organ, hard tissue, soft tissue, or lymph node. In some embodiments, the target site is a solid tumor or a portion thereof. As described above, the surgical article can be loaded with an amount of one or more therapeutic agents that effectively provides a therapeutic dose of one or more agents in situ to the target site for a period of time ranging from several weeks, months, or years.

[0139] In some embodiments, the subject in need of treatment is a human patient diagnosed with 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, cancer of nervous tissue, head and neck cancer, colon cancer, stomach cancer, bronchial cancer, kidney cancer, basal cell carcinoma, ulcerative and papillary squamous cell carcinoma, metastatic skin cancer, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small cell lung tumor, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumor, hair cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuroma, enteric ganglionoma, hyperplastic corneal neuroma, marfanoid habitus tumor, Wilms tumor (Wilm's tumors, seminoma, ovarian tumors, cervical dysplasia and carcinoma in situ, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, mycosis fungoides, rhabdomyosarcoma, Kaposi sarcoma, osteogenic and other sarcomas, renal cell tumors, 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 cystanoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, and nodular regenerative hyperplasia.

[0140] In some embodiments, the cancer is metastatic. In some embodiments, the cancer is non-metastatic. In some embodiments, the cancer is an advanced localized cancer. In some embodiments, the cancer is a recurrent locally advanced cancer.

[0141] In embodiments, the biomaterials disclosed herein can be used to treat subjects with malignant cancer or advanced cancer. In some embodiments, the subject in need of treatment can also be a subject that is unresponsive or refractory to currently available therapies or to the standard of care therapy for the disease, disorder or condition being treated, such as cancer.

[0142] 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 develops in the colon or rectum. In some embodiments, the biomaterial for treating colon cancer includes a therapeutic agent indicated for treating colon cancer. In some embodiments, the biomaterial includes a therapeutic agent selected from gemcitabine (Gemzar), raltitrexed (Tomudex TM ), Oxaliplatin (Eloxatin TM ), regorafenib, irinotecan (Camptostar TM ) and 5-fluorouracil (Adrucil TM ) In some embodiments, the therapeutic agent is selected from capecitabine, fluorouracil, irinotecan and oxaliplatin, and combinations thereof.

[0143] In some embodiments, treating cancer according to the methods described herein results in elimination of symptoms or complications of the cancer being treated. Symptoms need not be eliminated. In some embodiments, the severity of the symptoms is reduced. In the case of cancer, non-limiting examples of such symptoms include clinical markers of severity or progression, including the extent to which the tumor secretes growth factors, degrades the extracellular matrix, vascularizes, loses adhesion to juxtaposed tissues, or metastasizes, and the number of metastases.

[0144] Treatment of cancer according to the methods described herein may result in a reduction in tumor size. A reduction in tumor size may also be referred to as tumor regression. In some embodiments, after treatment, the tumor size is reduced by at least about 5% relative 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, tumor size may be measured as the diameter of the tumor.

[0145] Treatment of cancer according to the methods described herein can result in a reduction in tumor volume. In some embodiments, after treatment, the tumor volume is reduced by at least about 5% relative 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.

[0146] Treatment of cancer according to the methods described herein can result in a reduction in the number of tumors. Relative to the number of tumors before treatment, the number of tumors can be reduced, for example, 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%. The number of tumors can be measured by any reproducible measurement. The number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x magnification).

[0147] Treatment of cancer according to the methods described herein can result in a reduction in the number of metastatic lesions in tissues or organs outside the primary tumor site. Relative to the number of metastatic lesions before treatment, metastatic lesions can be reduced, for example, 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%. The number of metastatic lesions can be measured by any reproducible measurement. The number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x or 50x magnification).

[0148] Compared to a population receiving a carrier alone, treating cancer according to the methods described herein can result in an increase in the average survival time of the treated population. The increase in the average survival time of the population can be measured by any reproducible method. The increase in the average survival time of the population can be measured, for example, by calculating the average survival length of the population after starting treatment with an active compound (e.g., implanting a biomaterial loaded with a therapeutic agent). The increase in the average survival time of the population can also be measured, for example, by calculating the average survival length of the population after completing the first round of treatment with an active compound. In some embodiments, the average survival time of the population increases by at least 30 days, at least 60 days, at least 90 days, or at least 120 days.

[0149] Compared to a group receiving standard care therapy, treating cancer according to the methods described herein can result in an increase in the average survival time of the treated subject group. In some embodiments, the average survival time of the group increases by at least 30 days, at least 60 days, at least 90 days, or at least 120 days. The increase in the average survival time of the group can be measured by any reproducible method. The increase in the average survival time of the group can be measured, for example, by calculating the average survival length of the group after starting treatment with an active compound (e.g., implanting a biomaterial loaded with a therapeutic agent). The increase in the average survival time of the group can also be measured, for example, by calculating the average survival length of the group after completing the first round of treatment with an active compound.

[0150] Compared to a population receiving a carrier alone, treating cancer according to the methods described herein may result in a reduced mortality rate in the population of treated subjects. Compared to an untreated population, treating cancer according to the methods described herein may result in a reduced mortality rate in the population of treated subjects. Compared to a population receiving standard care therapy, treating cancer according to the methods described herein may result in a reduced mortality rate in the population of treated subjects. For example, the mortality rate may be reduced by at least about 2%, at least about 5%, at least about 10%, or at least about 25%. The reduction in the mortality rate of the population of treated subjects may be measured by any reproducible method. The reduction in the mortality rate of the population may be measured, for example, by calculating the average number of disease-related deaths per unit time after the population begins treatment with an active compound. The reduction in the mortality rate of the population may also be measured, for example, by calculating the average number of disease-related deaths per unit time after the population completes the first round of treatment with an active compound.

[0151] Treatment of cancer according to the methods described herein can result in a reduction in tumor growth rate. In some embodiments, the methods disclosed herein reduce 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%, relative to the amount before treatment. Tumor growth rate can be measured by any reproducible measurement. Tumor growth rate can be measured based on the change in tumor diameter per unit time. In some embodiments, the tumor growth rate after treatment can be about zero and is determined to remain the same size, i.e., has stopped growing.

[0152] Treatment of cancer according to the methods described herein can result in reduced tumor regrowth. In some embodiments, treatment with the methods disclosed herein results in tumor regrowth of up to about 5%, up to about 10%, up to about 20%, up to about 30%, up to about 40%, up to about 50%, or up to about 75%. For example, tumor regrowth is measured by measuring an increase in tumor diameter after a previous tumor reduction after treatment. No tumor recurrence after treatment has stopped indicates reduced tumor regrowth.

[0153] Ways to treat pain

[0154] The present disclosure also provides a method for treating or controlling pain in a subject in need thereof, the method comprising implanting a biomaterial as described herein into a target site of the subject. In some embodiments, the target site is nerve, connective tissue, and skeletal muscle and tissue. As described above, the biomaterial can be loaded with a certain amount of one or more therapeutic agents, which effectively provide a therapeutically effective amount of one or more therapeutic agents in situ to the target site for a period of time ranging from several weeks, months, to several years. In some embodiments, the subject in need thereof is a human patient who needs to treat postoperative pain, peripheral nerve injury, or chronic low back pain. In some embodiments, the subject needs to treat or control pain associated with osteoarthritis, diabetic peripheral neuropathy, or musculoskeletal injury or trauma.

[0155] In some embodiments, for the treatment of pain as 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 derivatives thereof.

[0156] In some embodiments of the methods described herein for treating pain, the one or more therapeutic agents is dexamethasone, ondansetron, acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), gabapentin, pregabalin, capsaicin, ketamine, memantine, clonidine, dexmedetomidine, tapentadol, transdermal fentanyl, a long-acting local anesthetic, a cannabinoid, or a combination of any of the foregoing.

[0157] Example

[0158] In some embodiments, the biomaterials (eg, biomaterial units) disclosed herein are described as "chips."

[0159] Example 1: Biomaterial Preparation

[0160] Overview

[0161] The biomaterial disclosed in this embodiment herein is a 3D printing platform designed for local delivery of drugs at tumor sites. This strategy aims to avoid clinical side effects caused by systemic toxicity of chemotherapeutic drugs. Biomaterials are organized structures of pores and drug concentration areas. This entropy of drug distribution can provide a key opportunity to adjust the drug release rate on demand and can be customized to deliver therapeutic doses for specific disease indications. Biomaterials can be original polymer and drug combinations, for example, without any additives or fillers, thereby reducing the possibility of immune response or crosstalk between various components. The polymer will disperse the drug in its matrix and deliver the drug in a slow and continuous manner. The release of the drug will be defined by different (e.g., optimized) combinations of polymer and drug properties.

[0162] Biomaterials can address the unmet needs for novel and platform drug delivery technologies. Conventional drug delivery systems may involve diffusion of drug particles throughout the bloodstream, which reduces the bioavailability of the drug at the target site. In addition, the mode of intake in conventional mechanisms involves significant decomposition of active ingredients or localization of action. Targeted drug delivery is gaining attention due to the huge demand for improving drug delivery efficiency and the need to alleviate potential side effects that may occur due to drug accumulation. With the emergence of nanotechnology and biocompatible materials, targeted drug delivery technology has begun to accelerate development. Targeted drug delivery can have a high impact and adoption potential due to its ability to improve bioavailability and organ specificity. This trend can potentially lead to the adoption of technologies such as organ-specific delivery, cell simulation, guided delivery, and spatiotemporal control systems.

[0163] background

[0164] This embodiment relates to drug formulation for local delivery of drugs (e.g., 5-fluorouracil, gemcitabine, etc.) for the treatment of pancreatic cancer using 3D printed polymer structures.

[0165] Millions of people worldwide suffer from cancer. Of them, thousands die every day. Pancreatic cancer is one of the deadliest cancers, with a mortality rate of 85%. According to the American Cancer Society, there are an estimated 60,430 new cases of pancreatic cancer in 2021 alone [Cancer Facts & Figures 2021]. Symptoms appear in the late stages of cancer, when the cancer reaches stage three or four in the patient by then. The chances of survival are slim to none. The current standard of care is to remove the tumor through a clinical procedure called 'pancreaticoduodenectomy' or Whipple procedure. During the operation, a portion of the pancreatic head, duodenum, bile duct, and gallbladder are removed to prevent any removal of the tumor. The five-year survival rate is 27.4% [Improved Survival Following Pancreaticoduodenectomy to Treat Adenocarcinoma of the Pancreas The Influence of Operative Blood Loss]. However, surgery is not an option for most patients diagnosed with pancreatic cancer.

[0166] Chemotherapy is another treatment approach for pancreatic cancer patients. Chemotherapy is administered before surgery (neoadjuvant chemotherapy) to reduce the size of the tumor so that it can be removed, or chemotherapy is administered after surgery (adjuvant chemotherapy) to prevent any growth of residual tumor cells or tumor resection. When surgery is no longer feasible, chemotherapy will also be administered to patients. Anti-tumor drugs (such as 5-fluorouracil, gemcitabine (2', 2'-difluoro 2' deoxycytidine, dFdC) or gemcitabine hydrochloride) can be a treatment modality administered intravenously. For example, the standard clinical dose of gemcitabine is 1000 mg / m2 infused into the patient by IV over 30 minutes. 2 . The administration can be performed weekly for 7 consecutive weeks, followed by a one-week break, and then 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, flu-like symptoms, bone marrow suppression, pulmonary toxicity, and peripheral edema [Gemcitabine-Induced Pulmonary Toxicity: A Case Report of Pulmonary Veno-Occlusive Disease]. Recently, a drug combination, for example, a chemotherapy regimen including folinic acid, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin has been clinically used for the treatment of pancreatic cancer. Despite the improved survival rates compared to surgery and gemcitabine treatment, there are reported serious side effects with chemotherapy regimens, including: hair loss, redness, pain or peeling of the palms and soles, rash, increased risk of sunburn, itching, severe diarrhea, nausea, vomiting, constipation, loss of appetite, weight loss, difficulty swallowing, mouth sores, heartburn, infection (especially when the white blood cell count is low), anemia that may require a blood transfusion, bruising, bleeding, headache, fatigue, weakness, dizziness, numbness, tingling or pain, a "pins and needles" feeling in your hands, feet, arms, and legs, tingling or loss of feeling in your hands, feet, nose, or tightness in the throat or jaw, or difficulty swallowing or breathing (which may be made worse by exposure to cold, cough, shortness of breath, fever, and pain). Regardless of which chemotherapy is administered, side effects caused by the systemic toxicity of these drugs can be very common in pancreatic cancer patients. The rapid availability of the drug in the bloodstream may be associated with diffusion throughout most of the body and the effects of the drug on normal cells, while only a small portion of the drug reaches the cancer cells. The deleterious effects of drugs on healthy cells may be the main cause of several serious side effects in patients. The purpose of drug delivery treatment strategies can be to deliver therapeutic doses that are effectively available at the disease site. Therefore, biomaterials disclosed herein can promote the sustained release of drugs (e.g., 5-fluorouracil, gemcitabine, etc.) locally at pancreatic tumor sites, thereby reducing the availability of drugs to healthy cells.

[0167] The technology disclosed herein provides a combined solution to the problem of surgery and chemotherapy and can be performed in parallel with standard of care surgery. Innovations in component materials and ultra-microstructures achieved through 3D printing allow the product prototype to release more stably over a longer time scale than previous iterations, which may allow the desired effect to be achieved with a single implant. By localizing the effects of chemotherapy, the biomaterial provides an alternative to direct surgical resection for delicate areas around the pancreas. We anticipate that this will expand the number of patients who can benefit from surgery and improve the overall success of the surgery, primarily by preventing local recurrence. Overall, the sustained and localized release properties of the biomaterial may improve surgical and chemotherapy outcomes for PC. Healthcare costs may also be reduced by reducing chemotherapy side effects and the need for hospitalization for chemotherapy.

[0168] Drug delivery therapeutic strategies involve incorporating drugs into polymer structures, which can be nanoparticles, microparticles, or scaffolds with two-dimensional or three-dimensional architectures that facilitate slow, sustained release of drugs in small quantities over a longer period of time. The polymer plays a major role in defining the amount and time of drug release from the polymer. The U.S. Food and Drug Administration has approved several biodegradable and biocompatible polymers such as polylactic acid-co-glycolide (PLGA), polycaprolactone (PCL), polyglycolide (PGA), polylactic acid (PLA), which are widely used in drug delivery applications. PCL blended with PLA is approved by the FDA as a safe food contact agent for packaging purposes. AQLANE Medical BV of the Netherlands produces a urethral implant under the trade name "Urolon", which is composed of 70% CMC gel and 30% PCL microspheres. PCL is a soft and 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 the molecular weight or number of molecules. The higher the molecular weight, the higher the viscosity. PCL has an average molecular weight ranging from 3000 to 90,000 g / mol. For this study, we used PCL with molecular weights of 25000, 37000, 50000 and 80000. The molecular weight of PCL plays a crucial role in drug release and degradation rate. PCL undergoes two steps of degradation: the first step is the hydrolytic cleavage of the ester groups, and the second step is the intracellular degradation of PCL with a molecular weight less than 3000. PCL degrades faster outside the human body due to the action of bacterial enzymes, rather than in the human body because these 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●) may be the main component of PCL degradation in implantable devices. Therefore, it is obvious that the molecular weight of PCL plays a major role in defining the release profile of the drug in the delivery device.

[0169] Technical Strategy

[0170] Drug release from polymers may be a key factor in the ability of biomaterials to provide therapeutic doses at tumor sites to promote tumor cell death. For example, the release of drugs can be controlled in two ways. The first way is to change the polymer molecular weight, which will affect the density and permeability properties of PCL. The second way is to change (e.g., optimize) the amount of drug loaded in the polymer. Taking these two factors into account, the following strategy was planned.

[0171] Strategy I: was used to test the effect of PCL molecular weight on drug release under uniform drug loading conditions.

[0172] Strategy II was used to test the effect of the molecular weight of PCL on the in vitro drug release profile in the presence of different drug loadings.

[0173] Both strategies lead to finding an effective (eg, optimized) formulation with a suitable polymer that can release the desired amount of drug.

[0174] Strategy 1: Gain a preliminary understanding of the effect of molecular weight on drug release.

[0175] The size of the polymer (e.g., the number average molar mass of the polymer, such as the number average molar mass of PCL) can have an effect on the release profile (e.g., release rate) of a drug (e.g., 5-fluorouracil, gemcitabine, etc.) from a biomaterial comprising a polymer as disclosed herein.

[0176] For example, PCL molecular weight may have an effect on the in vitro drug release profile. In order to evaluate this phenomenon, PCL with two different number average molar mass values ​​(e.g., 37,000 and 50,000) was selected to study with the anticancer drug 5-fluorouracil (5-FU) with an initial loading of 20 wt%. The sample of PCL with a number average molar mass of about 37,000 (i.e., PCL 37000, PCL 37k, or PCL 37) mixed with 20 wt% of gemcitabine was called "PG37", and the sample of PCL with a number average molar mass of about 50,000 (i.e., PCL 50000, PCL 50k, or PCL 50) mixed with 20 wt% of gemcitabine was called "PG50". Typically, the number average molar mass is Z×10 3 The PCL sample can be referred to as PCL Z×10 3 , PCL ZK or PCL Z.

[0177] Table 1: Preparations of PCL and 5-FU

[0178]

[0179] Hot Melt Extrusion: 1.6 g of polymer was mixed with 0.4 g of 5-fluorouracil and blended in a hot melt extruder (HAAKE mini-CTW, Thermoscientific, USA) using the following parameters.

[0180] Table 2: Blending parameters of PCL and 5-FU

[0181] parameter value temperature 75℃(PCL37000) 85℃(PCL50000) Blending (RPM) 200 Screw revolutions during extrusion (RPM) 50 Mixing time 15 minutes

[0182] 3D Printing : The blended formulation was placed into a metal syringe, and the biomaterial was 3D printed in an Allevi2 bioprinter (Allevi3D, 3D systems, USA) following the manufacturer's protocol.

[0183] Expansion : When a polymer is introduced into an aqueous environment, water diffuses into the polymer porous structure, causing the polymer to swell and increase in mass. The change in mass is called the percent swelling of the polymer and is given by the following equation:

[0184]

[0185] Where W D is the dry weight of the polymer, and W S is the expanded weight of a polymer, or the weight of a polymer at a point in time after it has been allowed to swell in a liquid.

[0186] After printing, the dry mass of each chip was measured in a weighing balance (Mettler Toledo, USA). In a falcon tube, 25 mL of 0.1 M phosphate buffered saline solution (PBS, pH 7.4) and the chip were introduced into the buffer solution and allowed to be incubated in a shaking bottle at 37 ° C and 250 rpm. After 24 hours, the chip was weighed. The chip was returned to the buffer solution and incubator and allowed to be further shaken for 7 days. The weight of the chip was measured and recorded.

[0187] 1. Drug Release

[0188] 2. Degradation

[0189] Strategy 2: Evaluate enhanced (eg, optimal) dose of polymer (eg, PCL) and drug (eg, 5-fluorouracil, gemcitabine) formulations and optimal molecular weight of polymer

[0190] Biomaterials can be generated with one or more polymers (e.g., PCL) and drugs (e.g., 5-fluorouracil, gemcitabine) at different weight ratios to evaluate, for example, manufacturing conditions, properties of the resulting biomaterial (e.g., drug release profile, stability, etc.). For example, biomaterials including different weight ratios of PCL and gemcitabine can be generated and analyzed.

[0191] Table 3: Formulations of PCL and gemcitabine (wt / wt)

[0192]

[0193] result

[0194] The results from the experiments conducted are that the lower molecular weight PCL of 25,000 and 37,000 are easy to mix with all the different weights of PCL and are easier to print compared to the 80,000 molecular weight PCL. Whereas the 50,000 molecular weight PCL is slightly easier to print than the 80,000 molecular weight PCL and is stiffer compared to the 25 and 37K PCL formulations. There is no significant difference in the release profile between the 37,000 and 50,000 molecular weight PCL after drug encapsulation and release. PCL with molecular weight less than 37,000 and greater than or equal to 50,000 can be used to customize the release profile, as the 80,000 molecular weight may be difficult to develop a formulation for.

[0195] Strategy 1:

[0196] Expansion Research

[0197] The dry mass and expanded mass of each sample were taken at 1 minute, 24 hours and 7 days. The percent expansion at the 24 hour time point and the 7 day time point was calculated according to equation (1). The average percent expansion for each sample and time point can be found in Table 4.

[0198] Table 4: Swelling percentage of biomaterial samples

[0199]

[0200] As can be seen from Table 4, the total percentage expansion among all samples ranged from 0% to 3.5%. The PCLdose2K sample had the largest increase in mass, with a percentage expansion of 3.5% after 24 hours and 3.05% after 7 days. In addition, the PG50 sample also had a higher percentage expansion than the PCL sample. On average, the percentage expansion after 7 days was greater than the percentage expansion at 24 hours (in comparison, for all samples, the total average expansion at day 7 was 1.55%, and the average expansion after 24 hours was 1.34%).

[0201] Degradation studies

[0202] Degradation curve Figure 6 It is shown that PF50 and PF37 degraded by about 27% over a 30-day period. However, the weight of the P50 and P37 controls did not decrease. This weight loss may be due to the release of the drug from the biomaterial. Regarding the correlation of weight loss with release, it can be confirmed that the degradation shown by the drug-loaded formulation is actually the release of the drug.

[0203] Release Research

[0204] The 30-day release study showed that both PF50 and PF37 showed sustained release ( Figure 7 PF50 showed higher 5-FU drug release compared to PF37. The release profiles between the two polymers were similar. The higher molecular weight polymer released a relatively increased drug dose. This higher release may be due to the high viscosity or relative hydrophobicity of the polymer.

[0205] Strategy 2:

[0206] In a hot melt extruder, formulations of PCL with different molecular weights (25,000 [F]; 37,000 [G]; 50,000 [H] and 80,000 [J]) were mixed with different weights of gemcitabine hydrochloride (45, 60, 80 and 125 mg / 100 mg PCL) to ensure uniform dispersion and mixing of the drug in the polymer. Under the set parameters, formulations with molecular weights of 25,000 and 37,000 processed smoothly with all different weights of gemcitabine. The formulation with a molecular weight of 50,000 showed some friction during mixing with 125 mg / 100 mg PCL. The process needed to be repeated again to ensure uniform mixing. The formulation with a molecular weight of 80,000 was extruded with gemcitabine with weights of 45 and 60 mg / 100 mg PCL and mixed repeatedly. However, no mixing and extrusion was observed for the 80,000 molecular weight PCL with 80 and 125 mg / 100 mg of gemcitabine. The results demonstrate that molecular weights of 25,000, 37,000, and 50,000 worked well with all the different weights of gemcitabine, providing uniform mixing and extrusion.

[0207] Extruded formulations were 3D printed using optimized printing parameters for different molecular weight PCL alone (without gemcitabine). However, for PCL with higher molecular weight loaded with larger amounts of gemcitabine, some adjustments were made in terms of temperature, pressure, and layer height. The lower molecular weight PCL of 25,000 printed all formulations with different weights of gemcitabine at higher printing speeds and lower pressures, while the higher molecular weight PCL of 80,000 was very difficult to print, and formulations greater than 45mg / 100mg PCL could not be printed in the 3D printer at all. For these 80K PCL-gemcitabine formulations, the temperature was increased to 120°C, and the printed chips showed color changes, indicating that some thermal degradation of the polymer had occurred.

[0208] preparation

[0209] The formulations of biomaterials disclosed herein may include one or more polymers (e.g., PCL) and a drug substance (e.g., 5-fluorouracil, gemcitabine), and, for example, the polymer molecular weight (e.g., number average molar mass) and / or active pharmaceutical ingredient (API) ratio are selected to allow controlled release of the drug substance after placement (e.g., within 4 weeks). These components may be uniformly combined and sterilely 3D printed.

[0210] Illustrative biological materials may include or consist of the following preparations:

[0211] The impermeable layer present in the biomaterial is constructed of PCL 50,000 (without drug). The permeable layer is PCL 37,000 (with optional drug) and PCL 50,000 (with optional drug). Various suitable compounds can be included in the formulation.

[0212] Additional (or alternative) embodiments of the biomaterials disclosed herein are Figure 8 , where darker shading may refer to the loading of one or more therapeutic agents (e.g., 5-fluorouracil, gemcitabine).

[0213] In some embodiments, such as Fig. 9As shown, the biomaterial disclosed herein can include multiple parts (e.g., N, S, W, E, etc.) that can contain a drug (e.g., 5-fluorouracil, gemcitabine). In some cases, the drug can be loaded into one or more of the multiple parts of the biomaterial. In some cases, the drug can be loaded into two or more of the multiple parts of the biomaterial. The two or more parts can include a first part and a second part, and the first part and the second part can be characterized by having (1) different polymers, (2) the same polymer but with different number average molecular weights, (3) different drugs, (4) the same drug but with different loading amounts, and / or (5) different weight ratios between polymer and drug in each part.

[0214] In some embodiments, the biomaterial can be loaded with a drug (e.g., 5-fluorouracil) in four different parts (N, S, E, and W). Parts N and S can have substantially the same parameters: (i) including a high molecular weight polymer (e.g., PCL having a number average molecular weight of about 50,000 Daltons), and (ii) including substantially the same ratio between such polymer and loaded drug (e.g., a weight ratio of about 1:0.73 (polymer:drug), such as about 19 mg PCL and about 14 mg drug). In addition, parts E and W can have substantially the same parameters: (i) including a low molecular weight polymer (e.g., PCL having a number average molecular weight of about 37,000 Daltons), and (ii) including substantially the same ratio between such polymer and loaded drug (e.g., a weight ratio of about 1:0.50 (polymer:drug), such as about 12 mg PCL and about 6 mg drug). The biomaterial can include an additional region (e.g., a frame) surrounding at least a portion of one or more of the four different parts, and the additional region can be loaded with a drug. The additional region can be characterized as (i) comprising a high molecular weight polymer (eg, PCL having a number average molecular weight of about 50,000 Daltons and 45 mg of such polymer), and (ii) being substantially free of drug.

[0215] In some embodiments, the biomaterial can be loaded with a drug (e.g., 5-fluorouracil) in one or more of four different sections (N, S, E, and W). Sections N and S can have substantially the same parameters: (i) include a high molecular weight polymer (e.g., PCL having a number average molecular weight of about 50,000 Daltons), and (ii) include substantially the same ratio between such polymer and the loaded drug (e.g., a weight ratio of about 2:0.73 (polymer:drug), such as about 40 mg of PCL and about 14 mg of drug). Additionally, sections E and W can have substantially the same parameters: (i) include a low molecular weight polymer (e.g., PCL having a number average molecular weight of about 37,000 Daltons), and (ii) include substantially the same ratio between such polymer and the loaded drug (e.g., a weight ratio of about 2:0.50 (polymer:drug), such as about 24 mg of PCL and about 6 mg of drug). The biomaterial can include an additional region (e.g., a framework) surrounding at least a portion of one or more of the four different sections, and the additional region can be loaded with a drug. The additional region can be characterized by (i) including a high molecular weight polymer (e.g., PCL having a number average molecular weight of about 50,000 Daltons and 90 mg of such polymer), and (ii) being substantially drug-free.

[0216] Table 5

[0217]

[0218] If the drug molecule has an overly high (>>) weight, a lower molecular weight polymer can be used for the permeable layer (the ability to have more pores).

[0219] If the drug molecule has an overly low (<<dKA) weight, a higher molecular weight polymer can be used for the permeable layer.

[0220] For the impermeable layer, 50,000 MW will be the standard weight.

[0221] In some embodiments, additional aspects of the biomaterials disclosed herein can be varied for drug loadability, including but not limited to the size of the polymer of the biomaterial, the size of the therapeutic agent, the polarity (or charge) of the biomaterial, the polarity (or charge) of the therapeutic agent, and / or the printability of the polymer of the biomaterial and / or the therapeutic agent (e.g., the ability to withstand the manufacturing process and temperature).

[0222] Example 2: Overview of Dosage Forms, Manufacture, and Administration

[0223] Dosage form: Biomaterial-5-FU is a flexible sustained-release biodegradable dosage form consisting of fluorouracil encapsulated in a pure polymer matrix (polycaprolactone, PCL). Each Biomaterial-5-FU (20 mg) contains 20 mg of fluorouracil. A two-dimensional image of the chip design is shown in Fig.13 and the photos are shown in Fig.14 middle.

[0224] Approximate dimensions of biomaterial-5-FU:

[0225] L×W×H: 20mm×20mm×0.8mm

[0226] The mass is about 200 mg

[0227] Brief Overview of the Manufacturing Process: The biomaterials were produced using an additive manufacturing (AM) multi-extruder printing system that uses three reservoirs filled with biodegradable polymers or polymer-drug mixtures. The printer deposited the materials listed in Table 5 in a very precisely controlled spatial organization to form a structure containing four drug compartments. For the biomaterial-5-FU, two compartments contained the active pharmaceutical ingredient (API; see Fig.13 , darkest shade) of PCL-37,000 kDa MW, and both compartments contain Fig.13 , with medium dark shading in the center) of PCL-50,000 kDa MW, and the 50,000 kDa MW support material alone (see Fig.13 : light shade).

[0228] Table-6 Distribution of 5-FU in the biomaterial-5-FU region

[0229]

[0230] Administration route: Implant / place the biomaterial near the tumor. More than one chip can be implanted by connecting one biomaterial to another by sewing the angular hexagonal structures together. The biomaterial can be administered by methods utilizing endoscopy, colonoscopy, or traditional open surgery.

[0231] Example 3: Preclinical studies

[0232] The initial safety profile of the biomaterial, 5-FU, was established in a healthy rat model (BSPN001). The purpose of this study was to determine the total and local toxicity of the biomaterial when implanted subcutaneously. No major toxicological or safety issues were found. No total toxicity was found in the five major organs. Mild local inflammatory reactions consistent with a foreign body implant at the site were found in all 3 animals.

[0233] Efficacy was tested in a mouse model (BSPN02). The CT26 colorectal cell line in the mouse model was selected for in vivo toxicity and safety studies. The safety profile of the biomaterial-5-FU was compared with other control groups and evaluated from the following five aspects: (i) changes in body weight over time, (ii) organ weight and organ-to-body weight ratio, (iii) hematoxylin-eosin (H&E) staining for histological changes, (iv) liver function test panel, and (v) blood chemistry for evaluating the effect on the bone marrow. For H&E staining, five major organs (liver, heart, spleen, lung and kidney) were collected from mice at each time point. The biomaterial did not have any effect on the function of important organs including the cardiovascular, respiratory and central nervous systems. After the application of the biomaterial, no organs showed signs of local or systemic toxicity. Compared with intravenous push injection of 5-FU, the biomaterial showed a superior safety profile in short-term toxicity (p<0.05), as shown by blood chemistry. The study showed that there were no significant toxic effects, and the enzyme levels of all treatment groups were not statistically different from the untreated control group. Short-term whole blood toxicity 3 days after treatment showed differences in blood cell counts between the two groups (intravenous vs. biomaterial). The data suggest that IV 5-FU itself has toxic effects, as indicated by a decrease in the absolute number of white blood cells. This toxic effect was not observed in mice treated with biomaterial-5-FU. For animals treated with systemic (intravenous) 5-FU, white blood cell subsets showed signs of potential toxicity: a decrease in the number of monocytes and other white blood cells, indicating bone marrow suppression. This toxic effect was not observed in mice treated with biomaterial-5-FU.

[0234] Treatment of biomaterials in CT26 colorectal mice showed delayed tumor growth and statistically significant reduction in tumor burden. Preclinical non-GLP efficacy studies also showed that local 5-FU was continuously released into the subcutaneous CT26 colorectal cancer mouse model. Compared with blank biomaterials or no intervention, mice treated with biomaterial-5-FU showed minimal increase in tumor weight, and the tumor burden was significantly less than that of untreated and blank chips (P<0.05). Compared with mice in the group that did not receive 5-FU (untreated group and blank biomaterial group), mice in the group that received 5-FU (biomaterial-5-FU and 5-FU unconfigured chip) showed slower tumor growth. This was demonstrated by the smaller increase in tumor weight. By the 19th day, biomaterial-5-FU showed a strong anti-tumor effect compared with other interventions.

[0235] Dose escalation toxicity was tested in a large porcine model (BSPN003) with up to 5 units of biomaterial placed in the peritoneal cavity. In a 3-day study, the safety profile of the biomaterial-5-FU was determined by: (i) changes in body weight over time, (ii) changes in defecation or displacement of the biomaterial, (iii) gross pathological changes, (iv) hematoxylin-eosin (H&E) staining for histological changes, and (v) blood chemistry at the following time points: pre-dose, 8 hours, 16 hours, 24 hours, 32 hours, 40 hours, 48 ​​hours, and 72 hours. Five major organs (liver, heart, spleen, lung, and kidney) were collected from pigs at the end of the study for H&E staining. No organs showed signs of local or systemic toxicity after application of the biomaterial. No changes in body weight over time were found. No changes in defecation were observed. No displacement of the biomaterial surgically applied to the luminal surface of the intestine occurred. No blood chemistry tests showed signs of systemic toxicity or dose-related systemic toxicity. Gross examination of five major organs (liver, heart, spleen, lung and kidney) revealed no abnormalities. At the highest dose (5 biomaterial units), no systemic adverse reactions or significant local toxicity were found. In addition to local inflammation (<1 mm) found by visual inspection at the implantation site at autopsy, no significant toxicological, neurological or histological findings were observed in the in vivo study.

[0236] These studies establish nonclinical proof of principle. Collectively, these preclinical studies support the concept that biomaterials are a safe and effective local delivery system with minimal dose-limiting systemic adverse effects.

[0237] Table 7

[0238]

[0239] Example 4: GLP toxicity study

[0240] A GLP toxicology study was conducted on the biomaterial disclosed herein using Yucatan miniature pigs to evaluate the local tolerance of fluorouracil and determine whether the acute immune response will cause rejection and / or toxicity. Survival rate, acute mortality and / or the effect on overall survival / morbidity were observed over a duration of 28 days. The purpose of the GLP toxicity study was to evaluate the total organ toxicity, systemic exposure, systemic toxicity, local exposure and local toxicity of the biomaterial-5-FU. The primary endpoints included overall observations from autopsy, toxicology, histological analysis and pharmacokinetic analysis.

[0241] Before administration / surgery, blood samples for toxicokinetic evaluation will be collected from all animals, and then collected again at 8, 16, 24, 32, 40 and 48 hours and the 3rd, 4th, 5th, 6, 7, 14, 21 and 28 days after surgery. A total of 324 samples will be processed for analysis of the level of fluorouracil (API) by high-sensitivity liquid chromatography-mass spectrometry (LC-MS). This will be further used to show that biomaterial-5-FU will release API in a slow and continuous manner over the course of 28 days, and dose dumping will not occur. Pharmacokinetics will be evaluated at the 7th, 14th, 21st and 28th days by tissue analysis of 5-FU at the insertion site (and surrounding tissues, including lymph nodes). The analysis will be performed by high-sensitivity LC-MS.

[0242] Evidence of local toxicity can be observed, and there are no significant broader regional or systemic effects. Samples for clinical pathology will be collected before surgery, 3, 7, 14, 21 and 28 days after surgery. Images of gross tissues, before and after biomaterial placement and before and after surgical removal of biomaterials will be taken. Samples will be analyzed for serum chemistry (including amylase), hematology (including reticulocytes) and coagulation parameters (PT, APTT and fibrinogen). A complete autopsy will be performed on all animals, and selected tissues will be retained and the heart, kidney, liver, pancreas, spleen, stomach, thymus and surrounding tissues around the biomaterial placement will be weighed. H&E staining and histopathological evaluation will be performed.

[0243] Procedure - For all groups, the biomaterial will be implanted directly onto the rectal lining via endoscopy / colonoscopy of the animals. If this is not possible due to the anatomy of the animal, the biomaterial / 5FU will be implanted onto the rectal lining via open surgery.

[0244] Outcome Measures - Measures of success and acceptance criteria may include mortality of pigs. Measures of success and acceptance criteria may include drug tolerance of pigs. Histological samples at the site of biomaterial placement will be evaluated to look for necrosis or immune response immediately at the site of application. Local drug release will be evaluated to establish pharmacokinetics in the animal. Success criteria may include all pigs remaining alive prior to the point of sacrifice, showing no signs of infection, immune response or rejection, and generally remaining in good condition.

[0245] Criteria for early termination may include severe adverse clinical signs indicating necrosis or organ failure, the animal being moribund, or being in severe pain or distress.

[0246] Example 5: Clinical study

[0247] Human subjects (patients) with progressive, locally advanced rectal and anal cancer were selected.

[0248] Initial evaluation and feasibility studies will be performed at the time of implantation by visual inspection and the judgment of the principal investigator. To ensure continued placement of the biomaterial, a pelvic X-ray will be performed at week 2 of the maximum duration of application of 4 weeks in Cohort 1. Final evaluation of placement will be performed at the end of the 4-week treatment period after removal of the biomaterial. Criteria for repeat application will depend on clinical results from Part 1 and the judgment of the clinician.

[0249] In the current guidelines (ASCO, 2022), there are multiple time points in the treatment of this patient population that allow for safety evaluation. In general, locally advanced rectal cancer receives new adjuvant therapy (TNT chemotherapy followed by radiotherapy or chemotherapy after radiotherapy). The goal of TNT is to reduce tumor burden and potentially downstage the tumor before surgical resection. The initial evaluation of this patient population includes a physical examination, imaging by MRI, and then endoscopic evaluation. If radiotherapy is the initial treatment, another MRI, PE, and endoscopy are recommended after therapy (e.g., for a short 5-day radiotherapy, a time point one month later; for a long 5-week radiotherapy, it may be necessary to wait 6-8 weeks for evaluation). For short-term radiotherapy (5-day course), follow-up evaluation is performed after one month. For long-term radiotherapy (5-week course), follow-up is performed after 6-8 weeks. Regardless of the duration, most patients can undergo systemic chemotherapy one month after the course of radiotherapy. The transition period between radiotherapy and chemotherapy may be an opportunity window for the use of the biomaterial-5-FU.

[0250] The incidence of dose-limiting toxicities (DLTs) will be assessed and compared to DLTs associated with systemic delivery, e.g., during the first four weeks of treatment. For grade 1, 2, and 3 local adverse events, treatment may continue. However, for grade 4 local adverse events, the biologic material will be removed. DLTs may include the following:

[0251]

[0252] At the set follow-up time points of Days 1, 2, 14, and 28, plasma pK analysis for 5-FU will be performed by LCMS to test if dose dumping is occurring and if there is sustained / minimal systemic presence of 5-FU. If any serious adverse events (SAEs) are reported, the plasma pK will be evaluated at that time. In addition, pK histological analysis will be performed by LCMS on resected tumors (whether planned or caused by SAEs). LC-MS can potentially detect picograms per mL, which can be observed systemically from topical applications of 5-FU.

[0253] The purpose of the PK sampling program is to quantify the systemic and tumor / tissue concentrations of 5-FU and its associated metabolites. Although systemic concentrations of 5-FU may be low or undetectable, using appropriately sensitive bioanalytical assays, a systemic PK sampling program can capture the initial release profile of 5-FU, sustained release, and clearance after removal of the biomaterial-5-FU. Tumor and tissue sampling is intended to determine 5-FU concentrations in target and surrounding tissues.

[0254] For example, plasma pharmacokinetic analysis of 5-FU was performed by LC-MS on days 1, 8, 15, 22, and 28 to evaluate the release profile of 5-FU over time and systemic exposure.

[0255] Sampling can be performed on day 0 before dosing, and then at 1, 2, 6, and 24 hours after insertion to evaluate initial dose dumping. Additional sampling will assess the accumulation and release monitoring of plasma 5-FU on days 8, 15, 22, and 28. In order to characterize the elimination of 5-FU from the system, post-removal pharmacokinetic sampling will be performed on day 28 (1, 2, 6, and 24 hours after removal).

[0256] Additional pharmacokinetic sampling can be performed upon removal of the biomaterial-5-FU by tumor and tissue biopsy. In subjects with local tolerability issues or subjects with unplanned removal, tumor and surrounding tissue biopsies can be performed.

[0257] Patients with known DPD deficiency may be tested prior to inclusion in the trial.

[0258] If any SAEs are reported, plasma PK samples will be collected at that time. In addition, PK analysis of resected tumors (whether planned or caused by SAEs) will be performed by LC-MS.

[0259] The biomaterial contains 20 mg 5-fluorouracil with a mean release profile of 75% over 4 weeks and an effective dose of 15 mg + / -. The biomaterial is evaluated for local antitumor effects. The dose can be escalated, for example, until local DLT occurs.

[0260] Table 9

[0261]

[0262] Cohort 3 may include subjects with bulky colorectal tumors. Depending on the observed results, this expansion cohort may allow further dose escalation.

[0263] The primary signs of effectiveness will be determined by changes in tumor size, number of R0 resections, incidence of DLTs (compared to DLTs with systemic chemotherapy), improvement in symptoms compared to baseline, improvement in quality of life, and potential downstaging of tumors as demonstrated by imaging modalities such as MRI / CT. To demonstrate the release rate from the biomaterial, LC-MS analysis will be performed on plasma at set intervals (see Assessment Schedule), and following removal of the tumor, the tissue will also be assessed for 5-FU concentrations by LC-MS.

[0264] Example 6: Pharmacokinetics

[0265] The pharmacokinetics of the biomaterial disclosed herein are tested in a large pig model with up to 5 biomaterial units placed in the peritoneal cavity. At the following time points, blood samples are collected to determine the concentration of systemic 5-FU: before administration, 8 hours, 16 hours, 24 hours, 32 hours, 40 hours, 48 ​​hours and 72 hours. In view of the local nature of the product and quantity of the API, the systemic exposure of 5-FU can be below the detection level, and most of the 5-FU concentration can be found locally around the biomaterial. The detailed information of the pharmacokinetic tissue analysis is as follows.

[0266] Table 10

[0267]

[0268] Example 7: In vitro drug release

[0269] The release characteristics of biomaterials were evaluated under 0.1M PBS at 37°C. Three biomaterial units were immersed in an aqueous environment. Biomaterial units were removed from PBS at 15 minutes, 30 minutes, 1 hour (1H), 2H, 4H, 6H, 8H, 12H, 24H, 48H, 72H (3rd day) and 4th, 5th, 6, 7, 9, 12, 14, 18, 21, 28 days (4th week), 5th, 6, 7, 8, 9, 10, 11, 12 weeks (3rd month), 4th, 5 and 6 months. The level of fluorouracil in PBS was determined by HPLC. An initial burst was seen within 24 hours, wherein 17% of 5-FU was released. By the 7th day, 50% of 5-FU had been released. By the 28th day, 75% of 5-FU was released from biomaterial-5-FU.

[0270] Table 11

[0271]

[0272] Embodiment 8: Manufacturing method

[0273] A drug substance was generated, which included 20 mg of 5-fluorouracil (5-FU) as an active agent (chemical name: 5-fluoro-1H-pyrimidine-2,4-dione; C4H3FN2O2). Polycaprolactone (PCL) was used as an excipient (chemical name: (1,7)-polyoxepan-2-one; (C6H 10 O2) n ). The molecular weight of PCL was 37,000 (PCL-37k) or 50,000 (PCL-50k). The weight of PCL used was 32 mg (PCL-37k) or 40 mg (PCL-50k).

[0274] The manufacturing process is carried out in a cleanroom environment with open product handling. These facilities are continuously monitored and the cleanrooms are designed according to EU Class D.

[0275] For a process run of about 100 chips, the batch scheme for the three intermediate materials used is:

[0276] Table 12

[0277]

[0278] The process of manufacturing biomaterials can be summarized as follows: Fig.15 as shown in .

[0279] Mixture of 5-FU and polymer

[0280] Three biomaterials were generated: 1) PCL 37k+API; 2) PCL 50k+API; and 3) PCL 50k (alone).

[0281] PCL (37 or 50 kDa) and 5-FU (if applicable) were mixed at a drug weight ratio of 20% by two gravimetric feeders (one was a Pharma 11 Twin Screw Feeder Mini Twin Gravimetric feeder and one was a Gravimetric Roto Tube Hygienic) designed for a hot melt extruder Pharma 11 (Thermo Fisher Scientific (Thermo Electron GmbH; Karlsruhe, Germany)).

[0282] Extrusion and intermediate storage

[0283] PCL-5-FU (or PCL alone) was extruded into threads with a diameter of approximately 2 mm using a hot melt extruder (Pharma 11 (Thermo Electron GmbH; Karlsruhe, Germany) or similar hot melt extruder), and then the threads were wound onto cleaned transparent PET spools using a filament winder from TheremoFisher with surfaces for hygienic contact with FDA-approved materials. The spools were placed in sealed PE or aluminum bags until further use.

[0284] QC: Visual inspection of samples of extruded material; analytical parameters to be tested for each batch (experimental and clinical) include (i) the amount of 5FU in the blend (wt %); and (ii) GPC (Mn, Mw, Mn / Mw).

[0285] Biomaterial printing

[0286] Preparation: Weigh the desired amount / range of extrusion material. Place each set of PCL and PCL-API composites in one of the three printer extrusion chambers.

[0287] Process: The biomaterial is produced by an extrusion-based additive manufacturing (AM) process in which three composition ratios of PCL and API are precisely deposited in specific three-dimensional spatial locations. This is accomplished by placing each set of PCL and PCL-API composites in one of three extrusion chambers and heating the chamber until the PCL reaches its glass transition temperature and is able to flow (approximately 100°C). Once the glass transition temperature is reached, a pneumatic system pushes the PCL and / or PCL-API composites through a stainless steel syringe tip and deposits the material precisely in pre-specified locations, thereby building the entire biomaterial construct layer by layer. By precisely extruding the material at the glass transition temperature, the extruded material transforms back into a completely solid state once it is extruded from the system (e.g., substantially upon extrusion from the system), resulting in very little geometric or structural variation between chips.

[0288] Successful manufacturing of biomaterials via AM is achieved through a specific, validated, and predetermined machine code that determines the motion, flow rates, and temperatures that will be achieved by the 3D printer for the entire duration of the printing process (roughly 10 minutes). The electromechanical systems that control 3D printers have many feedback loops, safety checks, and sensor systems that are used to keep the system within tight operating ranges in terms of material temperature, composition, spatial resolution, and mass flow rate. The correct operation of these systems can therefore be critical to the successful manufacturing of biomaterials, and in addition to the control systems built into the 3D printer, independent verification systems can be used to perform regular calibration checks to ensure that the system is always operating within acceptable values.

[0289] In some embodiments, the manufacturing methods disclosed herein include using a process in which three chambers are used to print discrete areas of biodegradable polymers or polymer-drug mixtures that characterize the biomaterial design and allow it to have the desired biodegradation behavior and drug release profile. For example, three chambers (each containing PCL37-5FU, PCL50-5FU, or PCL50 alone) are heated to 105°C, a point at which the polymer or polymer-drug mixture can flow, and pneumatic pressure is applied to expel the material from a nozzle fixed to a stainless steel chamber. The three different chambers allow for geometrically desired printing of 3 different materials, so the spatial deposition of each of the 3 different materials can be very precisely controlled.

[0290] QC: Visual inspection, measuring biomaterial dimensions (length, width, and thickness) and quality. These measurements can indicate whether the total amount of 5FU in the chip is within specification. Measure the amount of 5FU per chip. Monitor 5FU and polymer quality.

[0291] Primary Packaging

[0292] The biological material is placed in a clamshell blister. The blister is labeled. The blister is placed in an aluminum bag optionally with a silica bag and optionally purged with nitrogen before sealing. The pouch is labeled. Two operators perform a 100% visual inspection of the seal quality (e.g., detect the presence of creases). If the seal is considered defective, the biological material is removed from the pouch and the blister with the product is placed in a fresh pouch with a label and further processed as described herein.

[0293] Secondary Packaging

[0294] Ten biomaterials are packaged in a carton (approximate dimensions - e.g., 2" x 2" x 3"), and the carton is packaged in a transport vehicle (e.g., reusable cold cardboard). For example, ten biomaterial units are packaged in a carton (approximate dimensions - e.g., 7" x 4" x 6"), and no more than 50 cartons are packaged in a carton transport vehicle. A transport vehicle is a fixed-size box used during sterilization. Small quantities of 10 chip cartons can be transported to various clinical sites. Transportation of materials can be carried out at temperatures up to 75 degrees Fahrenheit.

[0295] Sterilization

[0296] After temporary release, the cassettes containing the biological material in the primary packaging are sent to the sterilizer for gamma irradiation. The transport vehicle cassettes can be gamma irradiated separately.

[0297] QC: The shipping kit can be opened and a subset of the chip packages evaluated for bioburden, endotoxin, and sterility. Upon product return, the gamma spot can be visually inspected and the sterilization certificate and dose report checked ( Fig.17 ).

[0298] The biomaterial can be supplied as a sterile, solid / flexible surgical product packaged in a clamshell blister, sealed in an aluminum bag (or, e.g., a silica bag), optionally purged with nitrogen before sealing, and labeled. For example, the label can include a serial or batch number, dosage, percentage of active drug (e.g., w / w, w / v, or v / v), and drug storage instructions (e.g., 15-25° C., do not freeze).

[0299] Example 9: Clinical study

[0300] Cohort 1 - These are the first patients in the expansion. This can include any subject, whether previously treated or not. For example, this cohort can be used to evaluate additional safety and efficacy in these previously treated patients. These patients can have advanced cancer and have already received multiple therapies and have failed treatment. These subjects can be patients with locally advanced cancer who have local recurrent disease.

[0301] Cohort 2 - for isolating the effect of biomaterials as a chemotherapy alternative. The subjects are patients with locally advanced cancer who have received long-term radiotherapy, so they receive post-radiotherapy treatment but have not yet received any chemotherapy. The main purpose of this cohort can be to observe the efficacy and safety of treatment in patients after radiotherapy and before chemotherapy.

[0302] Cohort 3 - To determine if the biomaterial has an effect on radiotherapy before chemotherapy. Includes patients with locally advanced cancer who are scheduled to receive a short course of radiotherapy. This cohort may include subjects with smaller localized tumors that can be easily reached after a short course (e.g., 5 days) of radiotherapy who have not yet received other chemotherapy.

[0303] Cohort 4 - Dose escalation colorectal cancer. For example, subjects can receive 6-8 units of biomaterial per subject. Patient population criteria can be the same as cohort 1 - any and all colorectal cancer patients who have received treatment. Evaluate the safety of increasing doses while evaluating potential early clinical benefits.

[0304] Example 10: Development of biomaterials

[0305] The prototype biomaterial was tested with a combination of various polymer molecular weights and various parameters (printing, design, drug weight, polymer weight, etc.). The formulation that produced the most suitable release curve and manufacturing suitability was selected. The ratio of the formulation was determined by performing several release curve experiments using HPLC. Then, the final formulation named biomaterial-5-FU underwent several in vitro studies to determine the chemical and mechanical properties of the final product. Encapsulation measurements, stimulated release under various pH (pH 1, pH 5, pH 7.4, pH 8, pH 10), dosage uniformity, tensile strength, forced degradation studies, mechanical integrity, compressive strength, release curve after degradation, and the effect of expansion on biomaterial-5-FU were studied. The experiments performed include the experiments shown in Table 13:

[0306] Table 13

[0307]

[0308]

[0309]

[0310]

[0311] Example 11: Clinical study

[0312] Table 14

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320] Implementation

[0321] Embodiment 1. A biomaterial comprising a plurality of geometric elements and a therapeutic agent, wherein:

[0322] a first geometric element of the plurality of geometric elements comprising a first polymer and the therapeutic agent, wherein at least a portion of the first geometric element is porous;

[0323] a second geometric element of the plurality of geometric elements comprises a second polymer, wherein at least a portion of the second geometric element is substantially non-porous;

[0324] said at least said portion of said first geometric element is adjacent to said at least said portion of said second geometric element; and

[0325] The first polymer or the second polymer has a number average molar mass greater than 6,000 Daltons (Da),

[0326] Optionally, wherein:

[0327] (A) the first polymer and the second polymer have a number average molar mass greater than 6,000 Da; and / or

[0328] (B) the number average molar mass of the first polymer is different from the number average molar mass of the second polymer,

[0329] Further optionally, wherein:

[0330] a. the number average molar mass of the second polymer is greater than the number average molar mass of the first polymer; and / or

[0331] b. the number average molar mass of the second polymer is less than the number average molar mass of the first polymer; and / or

[0332] (C) 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,

[0333] Further optionally, wherein:

[0334] a. said number average molar mass of said first polymer is at least about 10 kDa; and

[0335] / or

[0336] b. the number average molar mass of the first polymer is at most about 100 kDa;

[0337] and / or

[0338] (D) the number average molar mass of the second 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,

[0339] Further optionally, wherein:

[0340] a. the number average molar mass of the second polymer is at least about 10 kDa; and /

[0341] or

[0342] b. said number average molar mass of said second polymer is at most about 100 kDa; and

[0343] / or

[0344] (E) the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0345] Further optionally, wherein the first polymer comprises PCL; and / or

[0346] (F) the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0347] Further optionally, wherein the second polymer comprises PCL; and / or

[0348] (G) the therapeutic agent comprises an anticancer agent, an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin and / or an anti-inflammatory agent; and / or

[0349] (H) the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine and / or vinorelbine,

[0350] Further optionally, wherein the therapeutic agent comprises fluorouracil.

[0351] Embodiment 2. A biomaterial comprising a plurality of geometric elements and a therapeutic agent, wherein:

[0352] a first geometric element of the plurality of geometric elements comprising a first polymer and the therapeutic agent, wherein an amount of the therapeutic agent in the first geometric element is greater than 30% by weight of the first polymer, and wherein at least a portion of the first geometric element is porous;

[0353] A second geometric element of the plurality of geometric elements is formed from a second polymer, wherein at least a portion of the second geometric element is substantially non-porous; and

[0354] said at least a portion of said first geometric element is adjacent to said at least a portion of said second geometric element,

[0355] Optionally, wherein:

[0356] (A) the amount of the therapeutic agent in the first geometric element is greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90% or more by weight of the first polymer,

[0357] Further optionally, wherein said amount of said therapeutic agent in said first geometric element is greater than 35% by weight of said first polymer; and / or

[0358] (B) the amount of the therapeutic agent in the first geometric element is greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, 55%, 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90% or more by weight of the combination of the first polymer and the second polymer,

[0359] Further optionally, wherein said amount of said therapeutic agent in said first geometric element is greater than 35% by weight of said combination of said first polymer and said second polymer; and / or

[0360] (C) the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0361] Further optionally, wherein the first polymer comprises PCL; and / or

[0362] (D) the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0363] Further optionally, wherein the second polymer comprises PCL; and / or

[0364] (E) the therapeutic agent comprises an anticancer agent, an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin and / or an anti-inflammatory agent; and / or

[0365] (F) the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine and / or vinorelbine,

[0366] Further optionally, wherein the therapeutic agent comprises fluorouracil; and / or

[0367] (G) the first geometric element has a porosity of 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%, as determined by scanning electron microscopy, thermoporoscopy, and / or cryoporoscopy.

[0368] Embodiment 3. 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:

[0369] a first geometric element of the plurality of geometric elements comprising a first polymer and the therapeutic agent, wherein at least a portion of the first geometric element is porous;

[0370] a second geometric element of the plurality of geometric elements comprises a second polymer, wherein at least a portion of the second geometric element is substantially non-porous;

[0371] said at least said portion of said first geometric element is adjacent to said at least said portion of said second geometric element; and

[0372] The first polymer or the second polymer has a number average molar mass greater than 6,000 Daltons (Da),

[0373] Optionally, wherein:

[0374] (I) the first polymer and the second polymer have a number average molar mass greater than 6,000 Da; and / or

[0375] (J) the number average molar mass of the first polymer is different from the number average molar mass of the second polymer,

[0376] Further optionally, wherein:

[0377] a. the number average molar mass of the second polymer is greater than the number average molar mass of the first polymer; and / or

[0378] b. the number average molar mass of the second polymer is less than the number average molar mass of the first polymer; and / or

[0379] (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,

[0380] Further optionally, wherein:

[0381] a. said number average molar mass of said first polymer is at least about 10 kDa; and

[0382] / or

[0383] b. the number average molar mass of the first polymer is at most about 100 kDa;

[0384] and / or

[0385] (L) the number average molar mass of the second 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,

[0386] Further optionally, wherein:

[0387] a. said number average molar mass of said second polymer is at least about 10 kDa; and

[0388] / or

[0389] b. the number average molar mass of the second polymer is at most about 100 kDa;

[0390] and / or

[0391] (M) the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0392] Further optionally, wherein the first polymer comprises PCL; and / or

[0393] (N) the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0394] Further optionally, wherein the second polymer comprises PCL; and / or

[0395] (O) the therapeutic agent comprises an anticancer agent, an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin and / or an anti-inflammatory agent; and / or

[0396] (P) the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine and / or vinorelbine,

[0397] Further optionally, wherein the therapeutic agent comprises fluorouracil;

[0398] Further optionally, wherein the condition is cancer, optionally wherein the cancer is a solid tumor, colorectal cancer, rectal cancer, anal cancer, lower gastrointestinal tract cancer, pancreatic cancer, lung cancer, bone cancer, or locally advanced cancer;

[0399] Further optionally, wherein said administering comprises implanting said biomaterial into said subject in the vicinity of a tumor.

[0400] Embodiment 4. 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:

[0401] a first geometric element of the plurality of geometric elements comprising a first polymer and the therapeutic agent, wherein an amount of the therapeutic agent in the first geometric element is greater than 30% by weight of the first polymer, and wherein at least a portion of the first geometric element is porous;

[0402] A second geometric element of the plurality of geometric elements is formed from a second polymer, wherein at least a portion of the second geometric element is substantially non-porous; and

[0403] said at least said portion of said first geometric element is adjacent to said at least said portion of said second geometric element;

[0404] Optionally, wherein:

[0405] (H) the amount of the therapeutic agent in the first geometric element is greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, 70%, 75%, greater than 80%, greater than 85%, greater than 90% or more by weight of the first polymer,

[0406] Further optionally, wherein said amount of said therapeutic agent in said first geometric element is greater than 35% by weight of said first polymer; and / or

[0407] (I) the amount of the therapeutic agent in the first geometric element is greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, 55%, 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90% or more by weight of the combination of the first polymer and the second polymer,

[0408] Further optionally, wherein said amount of said therapeutic agent in said first geometric element is greater than 35% by weight of said combination of said first polymer and said second polymer; and / or

[0409] (J) the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0410] Further optionally, wherein the first polymer comprises PCL; and / or

[0411] (K) the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA) and / or polyethylene glycol diacrylate (PEGDA),

[0412] Further optionally, wherein the second polymer comprises PCL; and / or

[0413] (L) the therapeutic agent comprises an anticancer agent, an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin and / or an anti-inflammatory agent; and / or

[0414] (M) the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine and / or vinorelbine,

[0415] Further optionally, wherein the therapeutic agent comprises fluorouracil; and / or

[0416] (N) the first geometric element has a porosity of 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%, as determined by scanning electron microscopy, thermoporometry, and / or cryoporometry;

[0417] Further optionally, wherein the therapeutic agent comprises fluorouracil;

[0418] Further optionally, wherein the condition is cancer, optionally wherein the cancer is a solid tumor, colorectal cancer, rectal cancer, anal cancer, lower gastrointestinal tract cancer, pancreatic cancer, lung cancer, bone cancer, or locally advanced cancer;

[0419] Further optionally, wherein said administering comprises implanting said biomaterial into said subject in the vicinity of a tumor.

Claims

1. 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, wherein 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, wherein at least a portion of the second geometric element is substantially non-porous; (c) said at least said portion of the first geometric element is adjacent to said at least said 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).

2. The biomaterial of claim 1, wherein the first polymer and the second polymer have a number average molar mass greater 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. The biomaterial according to claim 3 , wherein the number average molar mass of the second polymer is greater than the number average molar mass of the first polymer. The biomaterial according to claim 3 , wherein the number average molar mass of the second polymer is smaller than the number average molar mass of the first polymer.

6. The biomaterial of claim 1, wherein 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, or at least or up to about 1,000 kDa.

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

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

9. The biomaterial of claim 1, wherein the number average molar mass of the second 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, or at least or up to about 1,000 kDa.

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

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

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

13. The biomaterial of claim 1, wherein the first polymer comprises PCL.

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

15. The biomaterial of claim 1, wherein the second polymer comprises PCL.

16. The biomaterial of claim 1, wherein the therapeutic agent comprises an anti-cancer agent.

17. The biomaterial of claim 1, wherein the therapeutic agent comprises an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin, and / or an anti-inflammatory agent.

18. The biomaterial of claim 1, wherein the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, or vinorelbine.

19. The biomaterial of claim 1, wherein the therapeutic agent comprises fluorouracil.

20. 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, wherein the amount of the therapeutic agent in the first geometric element is greater than 30% by weight of the first polymer, and wherein at least a portion of the first geometric element is porous; (b) a second geometric element of the plurality of geometric elements is formed from a second polymer, wherein at least a portion of the second geometric element is substantially non-porous; and (c) At least the portion of the first geometric element is adjacent to at least the portion of the second geometric element.

21. The biomaterial of claim 20, wherein the amount of the therapeutic agent in the first geometric element is greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or more, based on the weight of the first polymer.

22. The biomaterial of claim 20, wherein the amount of the therapeutic agent in the first geometric element is greater than 35% by weight of the first polymer.

23. The biomaterial of claim 20, wherein the amount of the therapeutic agent in the first geometric element is greater than 5% by weight of the combination of the first polymer and the second polymer.

24. The biomaterial of claim 20, wherein the amount of the therapeutic agent in the first geometric element is greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or more, based on the weight of the combination of the first polymer and the second polymer.

25. The biomaterial of claim 20, wherein the amount of the therapeutic agent in the first geometric element is greater than 35% by weight of the combination of the first polymer and the second polymer.

26. The biomaterial of claim 20, wherein the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

27. The biomaterial of claim 20, wherein the first polymer comprises PCL.

28. The biomaterial of claim 20, wherein the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

29. The biomaterial of claim 20, wherein the second polymer comprises PCL.

30. The biomaterial of claim 20, wherein the therapeutic agent comprises an anti-cancer agent.

31. The biomaterial of claim 20, wherein the therapeutic agent comprises an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin, or an anti-inflammatory agent.

32. The biomaterial of claim 20, wherein the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, or vinorelbine.

33. The biomaterial of claim 20, wherein the therapeutic agent comprises fluorouracil.

34. The biomaterial of claim 20, wherein the porosity of the first geometric element is 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%, as determined by scanning electron microscopy, thermoporometry, and / or cryoporometry.

35. 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, wherein 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, wherein at least a portion of said second geometric element is substantially non-porous; (c) said at least said portion of the first geometric element is adjacent to said at least said 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).

36. The method of claim 35, wherein the first polymer and the second polymer each have a number average molar mass greater than 6,000 Da.

37. The method of claim 35, wherein the number average molar mass of the first polymer and the number average molar mass of the second polymer are different.

38. The method of claim 35, wherein the number average molar mass of the second polymer is greater than the number average molar mass of the first polymer.

39. The method of claim 35, wherein the number average molar mass of the second polymer is less than the number average molar mass of the first polymer.

40. The method of claim 35, wherein 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, or at least or up to about 1,000 kDa.

41. The method of claim 35, wherein the number average molar mass of the first polymer is at least about 10 kDa.

42. The method of claim 35, wherein the number average molar mass of the first polymer is at most about 100 kDa.

43. The method of claim 35, wherein the number average molar mass of the second 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, or at least or up to about 1,000 kDa.

44. The method of claim 35, wherein the number average molar mass of the second polymer is at least about 10 kDa.

45. The method of claim 35, wherein the number average molar mass of the second polymer is at most about 100 kDa.

46. ​​The method of claim 35, wherein the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

47. The method of claim 35, wherein the first polymer comprises PCL.

48. The method of claim 35, wherein the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

49. The method of claim 35, wherein the second polymer comprises PCL.

50. The method of claim 35, wherein the therapeutic agent comprises an anti-cancer agent.

51. The method of claim 35, wherein the therapeutic agent comprises an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin, or an anti-inflammatory agent.

52. The method of claim 35, wherein the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, or vinorelbine.

53. The method of claim 35, wherein the therapeutic agent comprises fluorouracil.

54. The method of claim 35, wherein the condition is cancer.

55. The method of claim 35, wherein the condition comprises a solid tumor.

56. The method of claim 35, wherein the condition comprises colorectal cancer.

57. The method of claim 35, wherein the condition comprises rectal cancer.

58. The method of claim 35, wherein the condition comprises anal cancer.

59. The method of claim 35, wherein the condition comprises lower gastrointestinal tract cancer.

60. The method of claim 35, wherein the condition comprises pancreatic cancer.

61. The method of claim 35, wherein the condition comprises lung cancer.

62. The method of claim 35, wherein the condition comprises bone cancer.

63. The method of claim 35, wherein the condition comprises locally advanced cancer.

64. The method of claim 35, wherein the administering comprises implanting the biomaterial into the subject in the vicinity of a tumor.

65. 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, wherein the amount of the therapeutic agent in the first geometric element is greater than 30% by weight of the first polymer, and wherein at least a portion of the first geometric element is porous; (b) a second geometric element of the plurality of geometric elements is formed from a second polymer, wherein at least a portion of the second geometric element is substantially non-porous; and and (c) At least the portion of the first geometric element is adjacent to at least the portion of the second geometric element.

66. The method of claim 65, wherein the amount of the therapeutic agent in the first geometric element is greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or more, based on the weight of the first polymer.

67. The method of claim 65, wherein the amount of the therapeutic agent in the first geometric element is greater than 35% by weight of the first polymer.

68. The method of claim 65, wherein the amount of the therapeutic agent in the first geometric element is greater than 5% by weight of the combination of the first polymer and the second polymer.

69. The method of claim 65, wherein the amount of the therapeutic agent in the first geometric element is greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or more, based on the weight of the combination of the first polymer and the second polymer.

70. The method of claim 65, wherein the amount of the therapeutic agent in the first geometric element is greater than 35% by weight of the combination of the first polymer and the second polymer.

71. The method of claim 65, wherein the first polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

72. The method of claim 65, wherein the first polymer comprises PCL.

73. The method of claim 65, wherein the second polymer comprises polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactide-glycolic acid (PLGA), or polyethylene glycol diacrylate (PEGDA).

74. The method of claim 65, wherein the second polymer comprises PCL.

75. The method of claim 65, wherein the therapeutic agent comprises an anti-cancer agent.

76. The method of claim 65, wherein the therapeutic agent comprises an antimicrobial agent, an antibiotic, a local anesthetic or analgesic, a statin, or an anti-inflammatory agent.

77. The method of claim 65, wherein the therapeutic agent comprises capecitabine, cisplatin, carboplatin, cyclophosphamide, docetaxel, adriamycin, etoposide, fluorouracil, floxuridine, gemcitabine, ifosfamide, irinotecan, methotrexate, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, regorafenib, vincristine, or vinorelbine.

78. The method of claim 65, wherein the therapeutic agent comprises fluorouracil.

79. The method of claim 65, wherein the porosity of the first geometric element is 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%, as determined by scanning electron microscopy, thermoporometry, and / or cryoporometry.

80. The method of claim 65, wherein the condition comprises cancer.

81. The method of claim 65, wherein the condition comprises a solid tumor.

82. The method of claim 65, wherein the condition comprises colorectal cancer.

83. The method of claim 65, wherein the condition comprises rectal cancer.

84. The method of claim 65, wherein the condition comprises anal cancer.

85. The method of claim 65, wherein the condition comprises lower gastrointestinal tract cancer.

86. The method of claim 65, wherein the condition comprises pancreatic cancer.

87. The method of claim 65, wherein the condition comprises lung cancer.

88. The method of claim 65, wherein the condition comprises bone cancer.

89. The method of claim 65, wherein the condition comprises locally advanced cancer.

90. The method of claim 65, wherein the administering comprises implanting the biomaterial into the subject in the vicinity of a tumor.

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