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Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.

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In this paper, we introduce the design and manufacturing process of a transtibial orthopedic implant. We used medical-grade polyurethane polymer resin to fabricate a 3D porous architected implant with tunable isotropy, employing a high-speed printing method known as Continuous Liquid Interface Production (CLIP). Our objective is to enhance the weight-bearing capabilities of the bone structures in the residual limb, thereby circumventing the traditional reliance on a natural bridge. To achieve a custom-made design, we acquire the topology and morphology of the residual limb as well as the bone structure of the tibia and fibula, utilizing computed tomography (CT) and high-resolution 3D scanning. We employed a dynamic topological optimization method, informed by gait cycle data, to effectively reduce the mass of the implant. This approach, which differs from conventional static methods, enables the quantification of variations in applied forces over time. Using the Euler-Lagrange energy approach, we propose the equations of motion for a homologous multibody model with three degrees of freedom. The versatility of the Solid Isotropic Material with Penalization (SIMP) method facilitates the integration of homogenization methods for microscale porous architectures into the optimized domain. The design of these porous architectures is based on a bias-driven tuning symmetry isotropy of a Triply Periodic Minimal Surface (Schwarz Primitive surface). The internal porosity of the structure significantly reduces weight without compromising the isotropic behavior of the implant.

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Different printing technologies can be used for prosthetically oriented implant placement, however the influence of different printing orientations and steam sterilization remains unclear. In particular, no data is available for the novel technology Continuous Liquid Interface Production. The objective was to evaluate the dimensional accuracy of surgical guides manufactured with different printing techniques in vertical and horizontal printing orientation before and after steam sterilization. A total of 80 surgical guides were manufactured by means of continuous liquid interface production (CLIP; material: Keyguide, Keyprint), digital light processing (DLP; material: Luxaprint Ortho, DMG), stereolithography (SLA; Surgical guide, Formlabs), and fused filament fabrication (FFF; material: Clear Base Support, Arfona) in vertical and horizontal printing orientation (n = 10 per subgroup). Spheres were included in the design to determine the coordinates of 17 reference points. Each specimen was digitized with a laboratory scanner after additive manufacturing (AM) and after steam sterilization (134 °C). To determine the accuracy, root mean square values (RMS) were calculated and coordinates of the reference points were recorded. Based on the measured coordinates, deviations of the reference points and relevant distances were calculated. Paired t-tests and one-way ANOVA were applied for statistical analysis (significance p < 0.05). After AM, all printing technologies showed comparable high accuracy, with an increased deviation in z-axis when printed horizontally. After sterilization, FFF printed surgical guides showed distinct warpage. The other subgroups showed no significant differences regarding the RMS of the corpus after steam sterilization (p > 0.05). Regarding reference points and distances, CLIP showed larger deviations compared to SLA in both printing orientations after steam sterilization, while DLP manufactured guides were the most dimensionally stable. In conclusion, the different printing technologies and orientations had little effect on the manufacturing accuracy of the surgical guides before sterilization. However, after sterilization, FFF surgical guides exhibited significant deformation making their clinical use impossible. CLIP showed larger deformations due to steam sterilization than the other photopolymerizing techniques, however, discrepancies may be considered within the range of clinical acceptance. The influence on the implant position remains to be evaluated.

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Vat photopolymerization (VP), including stereolithography (SLA), digital light processing (DLP), and volumetric printing, employs UV or visible light to solidify cell-laden photoactive bioresin contained within a vat in a point-by-point, layer-by-layer, or volumetric manner. VP-based bioprinting has garnered substantial attention in both academia and industry due to its unprecedented control over printing resolution and accuracy, as well as its rapid printing speed. It holds tremendous potential for the fabrication of tissue- and organ-like structures in the field of regenerative medicine. This review summarizes the recent progress of VP in the fields of tissue engineering and regenerative medicine. First, it introduces the mechanism of photopolymerization, followed by an explanation of the printing technique and commonly used biomaterials. Furthermore, the application of VP-based bioprinting in tissue engineering was discussed. Finally, the challenges facing VP-based bioprinting are discussed, and the future trends in VP-based bioprinting are projected.

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PURPOSE: To evaluate the effects of 5 manufacturing technologies and 2 finish line designs on the trueness and dimensional stability of 3D-printed definitive dies at finish line regions under different storage conditions and time. MATERIAL AND METHODS: Preparation of light chamfer and round shoulder finish lines were adopted individually on two mandibular first molar typodont teeth and digitalized as standard tessellation language (STL) files. A total of 240 samples (192 AM definitive dies and 48 definitive conventional stone dies) in 20 groups (n = 12) were manufactured based on 2 finishing line designs (chamfer and shoulder), 5 manufacturing technologies (4 additively manufactured technologies and conventional stone die), and 2 storage conditions (light exposure and dark). The 4 additively manufactured (AM) technologies include a DLP 3D-printer, an economic LED 3D-printer, a CLIP 3D-printer, and an SLA 3D-printer. All the study samples were distributed into two storage conditions. Subsequently, samples were digitalized to STL files at 3 different time points (within 36 hours, 1-month, and 3-months). A surface matching software was used to superimpose the sample STL files onto the corresponding original STL files with the best-fit alignment function. The trueness of each printed and stone definitive dies and their dimensional stabilities were measured by the root mean square (RMS, in mm). A linear mixed-effects model was used to test the effects of the finish line design, manufacturing technology, storage condition, and storage time on RMS values (α = 0.05). RESULTS: While finish line designs had no significant effects [F(1, 220) = 0.85, p < 0.358], the manufacturing technologies [F(3, 220) = 33.02, p < 0.001], storage condition [F(1, 220) = 4.11, p = 0.044], and storage time F(2, 440) = 10.37, p < 0.001] affected the trueness and dimensional stability of 3D-printed dies at finish line regions. No significant interactions were found among the 4 factors. For the manufacturing technologies, Type IV stone groups and LCD 3D-printer groups had significantly higher RMS values than the other 3 printers (p < 0.001) with no significant differences between Type IV stone and LCD 3D-printer groups (p = 0.577). DLP 3D-printer groups had higher RMS values than both SLA 3D-printer groups and CLIP 3D-printer groups (p < 0.001). There were no significant differences between SLA 3D-printer groups and CLIP 3D-printer groups, p = 0.671. For the effects of storage conditions, RMS values were significantly higher in the groups stored with the direct light exposure than the ones stored in the dark, p = 0.044. In terms of the effects of storage time, the RMS values were significantly higher after 1-month storage, p = 0.002; and 3-month storage, p < 0.001, than the ones at the immediate postmanufacturing stage. However, the RMS values after 1-month and 3-month storage were not significantly different from each other (p = 0.169). CONCLUSIONS: Manufacturing technologies, storage conditions, and storage time significantly affected the trueness and dimensional stability of 3D-printed dies at finish line regions, while finish line designs had no significant effects. Among the AM technologies tested, all have produced either comparable or truer 3D-printed dies than the Type IV dental stone dies, and the CLIP and SLA 3D-printers produced the best outcomes. 3D-printed dies showed significant distortion after 1-month and 3-months storage, especially under light exposure storage conditions. These findings may negate the clinical need to preserve 3D-printed dies, and digital data should be preserved instead.

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Brachytherapy, which is the placement of radioactive seeds directly into tissue such as the prostate, is an important curative treatment for prostate cancer. By delivering a high dose of radiation from within the prostate gland, brachytherapy is an effective method of killing prostate cancer cells while limiting radiation dose to normal tissue. The main shortcomings of this treatment are: less efficacy against high grade tumor cells, acute urinary retention, and sub-acute urinary frequency and urgency. One strategy to improve brachytherapy is to incorporate therapeutics into brachytherapy. Drugs, such as docetaxel, can improve therapeutic efficacy, and dexamethasone is known to decrease urinary side effects. However, both therapeutics have high systemic side effects. To overcome this challenge, we hypothesized that we can incorporate therapeutics into the inert polymer spacers that are used to correctly space brachytherapy seeds during brachytherapy to enable local drug delivery. To accomplish this, we engineered 3D printed drug-loaded brachytherapy spacers using continuous liquid interface production (CLIP) with different surface patterns to control drug release. These devices have the same physical size as existing spacers, allowing them to easily replace commercial spacers. We examined these drug-loaded spacers using docetaxel and dexamethasone as model drugs in a murine model of prostate cancer. We found that drug-loaded spacers led to higher therapeutic efficacy for brachytherapy, and there was no discernable systemic toxicity from the drug-loaded spacers. STATEMENT OF SIGNIFICANCE: There has been high interest in the application of 3D printing to engineer novel medical devices. However, such efforts have been limited by the lack of technologies that can fabricate devices suitable for real world medical applications. In this study, we demonstrate a unique application for 3D printing to enhance brachytherapy for cancer treatment. We engineered drug-loaded brachytherapy spacers that can be fabricated using Continuous Liquid Interface Production (CLIP) 3D printing, allowing tunable printing of drug-loaded devices, and implanted intraoperatively with brachytherapy seeds. In combined chemotherapy and brachytherapy we are able to achieve greater therapeutic efficacy through local drug delivery and without systemic toxicities. We believe our work will facilitate further investigation in medical applications of 3D printing.

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Resolving microscopic and complex 3D polymeric structures while maintaining high print speeds in additive manufacturing has been challenging. To achieve print precision at micrometer length scales for polymeric materials, most 3D printing technologies utilize the serial voxel printing approach that has a relatively slow print speed. Here, a 30-µm-resolution continuous liquid interface production (CLIP)-based 3D printing system for printing polymeric microstructures is described. This technology combines the high-resolution from projection microstereolithography and the fast print speed from CLIP, thereby achieving micrometer print resolution at x103 times faster than other high-resolution 3D printing technologies. Print resolutions in both lateral and vertical directions were characterized, and the printability of minimum 30 µm features in 2D and 3D has been demonstrated. Through dynamic printing optimization, a method that varies the print parameters (e.g. exposure time, UV intensity, and dark time) for each print layer, overhanging struts at various thicknesses spanning 1 order of magnitude (25 µm - 200 µm) in a single print are resolvable. Taken together, this work illustrates that the micro-CLIP 3D printing technology, in combination with dynamic printing optimization, has the high resolution needed to enable manufacturing of exquisitely detailed and gradient 3D structures, such as terraced microneedle arrays and micro-lattice structures, while maintaining high print speeds.

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Surgery is an important treatment for cancer; however, local recurrence following macroscopically-complete resection is common and a significant cause of morbidity and mortality. Systemic chemotherapy is often employed as an adjuvant therapy to prevent recurrence of residual disease, but has limited efficacy due to poor penetration and dose-limiting off-target toxicities. Selective delivery of chemotherapeutics to the surgical bed may eliminate residual tumor cells while avoiding systemic toxicity. While this is challenging for traditional drug delivery technologies, we utilized advances in 3D printing and drug delivery science to engineer a drug-loaded arrowhead array device (AAD) to overcome these challenges. We demonstrated that such a device can be designed, fabricated, and implanted intraoperatively and provide extended release of chemotherapeutics directly to the resection area. Using paclitaxel and cisplatin as model drugs and murine models of cancer, we showed AADs significantly decreased local recurrence post-surgery and improved survival. We further demonstrated the potential for fabricating personalized AADs for intraoperative application in the clinical setting.

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Vaccination is an essential public health measure for infectious disease prevention. The exposure of the immune system to vaccine formulations with the appropriate kinetics is critical for inducing protective immunity. In this work, faceted microneedle arrays were designed and fabricated utilizing a three-dimensional (3D)-printing technique called continuous liquid interface production (CLIP). The faceted microneedle design resulted in increased surface area as compared with the smooth square pyramidal design, ultimately leading to enhanced surface coating of model vaccine components (ovalbumin and CpG). Utilizing fluorescent tags and live-animal imaging, we evaluated in vivo cargo retention and bioavailability in mice as a function of route of delivery. Compared with subcutaneous bolus injection of the soluble components, microneedle transdermal delivery not only resulted in enhanced cargo retention in the skin but also improved immune cell activation in the draining lymph nodes. Furthermore, the microneedle vaccine induced a potent humoral immune response, with higher total IgG (Immunoglobulin G) and a more balanced IgG1/IgG2a repertoire and achieved dose sparing. Furthermore, it elicited T cell responses as characterized by functional cytotoxic CD8+ T cells and CD4+ T cells secreting Th1 (T helper type 1)-cytokines. Taken together, CLIP 3D-printed microneedles coated with vaccine components provide a useful platform for a noninvasive, self-applicable vaccination.

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A recently developed three-dimensional (3D) gel-printing technology, namely continuous liquid interface production (CLIP), was utilized to fabricate supramolecular shape memory hydrogels with high resolutions and complex 3D geometries. The UV-curable ink for CLIP was composed of hydrogel precursors (alginate and acrylamide) and a photo-initiator (ammonium persulfate). As expected, the double network formed from ionically crosslinked alginate and covalently crosslinked polyacrylamide endowed the printed hydrogels with excellent mechanical properties. Meanwhile, due to the reversible metal-ligand coordination interaction, the hydrogel could be temporarily immobilized into an optional shape after introducing calcium ions and return to its original shapes upon ion removal, exhibiting ion-triggered shape memory effect. Moreover, the presence of ions greatly improved the conductivity of the resultant hydrogels. Such 3D printed versatile hydrogels with complex geometries demonstrated the potential for selected applications, particularly in load-bearing materials and flexible electronic devices.

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Three-dimensional (3D) printing parts with excellent resolution and high performance are of great significance for scientific and engineering applications. In this study, a novel photocurable cellulose acetate butyrate (PC-CAB) resin was synthesized for continuous liquid interface production (CLIP) to construct 3D objects with high resolution, tailored mechanical properties, excellent chemical resistance and thermal stability. Particularly, the tensile and flexural strength of the CLIP 3D printed specimen could reach 44.67 and 64.53 MPa, respectively. Their solvent resistance against various organic solvents and strong acidic/basic solutions was evaluated. As expected, the 3D prints could well maintain their structural integrity and exhibited very low swelling ratios owing to the photo-induced chemical crosslinking structure. Notably, even after immersion in methylene chloride or 1.0 M acid/alkali for 3 h, the 3D prints still showed excellent mechanical and thermal properties. Further study demonstrated that when PC-CAB in the CLIP ink was optimized to 20 wt% while the photoinitiator (PI) was 0.5 wt%, complex-structured 3D printed objects with high surface quality could be obtained under specific printing parameters.

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Microneedle patches, arrays of micron-scale projections that penetrate skin in a minimally invasive manner, are a promising tool for transdermally delivering therapeutic proteins. However, current microneedle fabrication techniques are limited in their ability to fabricate microneedles rapidly and with a high degree of control over microneedle design parameters. We have previously demonstrated the ability to fabricate microneedle patches with a range of compositions and geometries using the novel additive manufacturing technique Continuous Liquid Interface Production (CLIP). Here, we establish a method for dip coating CLIP microneedles with protein cargo in a spatially controlled manner. Microneedle coating mask devices were fabricated with CLIP and utilized to coat polyethylene glycol-based CLIP microneedles with model proteins bovine serum albumin, ovalbumin, and lysozyme. The design of the coating mask device was used to control spatial deposition and loading of coated protein cargo on the microneedles. CLIP microneedles rapidly released coated protein cargo both in solution and upon insertion into porcine skin. The model enzyme lysozyme was shown to retain its activity throughout the CLIP microneedle coating process, and permeation of bovine serum albumin across full thickness porcine skin was observed after application with coated CLIP microneedles. Protein-coated CLIP microneedles were applied to live mice and showed sustained retention of protein cargo in the skin over 72 h. These results demonstrate the utility of a versatile coating platform for preparation of precisely coated microneedles for transdermal therapeutic delivery.

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Mass customization along with the ability to generate designs using medical imaging data makes 3D printing an attractive method for the fabrication of patient-tailored drug and medical devices. Herein we describe the application of Continuous Liquid Interface Production (CLIP) as a method to fabricate biocompatible and drug-loaded devices with controlled release properties, using liquid resins containing active pharmaceutical ingredients (API). In this work, we characterize how the release kinetics of a model small molecule, rhodamine B-base (RhB), are affected by device geometry, network crosslink density, and the polymer composition of polycaprolactone- and poly (ethylene glycol)-based networks. To demonstrate the applicability of using API-loaded liquid resins with CLIP, the UV stability was evaluated for a panel of clinically-relevant small molecule drugs. Finally, select formulations were tested for biocompatibility, degradation and encapsulation of docetaxel (DTXL) and dexamethasone-acetate (DexAc). Formulations were shown to be biocompatible over the course of 175 days of in vitro degradation and the clinically-relevant drugs could be encapsulated and released in a controlled fashion. This study reveals the potential of the CLIP manufacturing platform to serve as a method for the fabrication of patient-specific medical and drug-delivery devices for personalized medicine.

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Despite the increasing popularity of 3D printing, also known as additive manufacturing (AM), the technique has not developed beyond the realm of rapid prototyping. This confinement of the field can be attributed to the inherent flaws of layer-by-layer printing and, in particular, anisotropic mechanical properties that depend on print direction, visible by the staircasing surface finish effect. Continuous liquid interface production (CLIP) is an alternative approach to AM that capitalizes on the fundamental principle of oxygen-inhibited photopolymerization to generate a continual liquid interface of uncured resin between the growing part and the exposure window. This interface eliminates the necessity of an iterative layer-by-layer process, allowing for continuous production. Herein we report the advantages of continuous production, specifically the fabrication of layerless parts. These advantages enable the fabrication of large overhangs without the use of supports, reduction of the staircasing effect without compromising fabrication time, and isotropic mechanical properties. Combined, these advantages result in multiple indicators of layerless and monolithic fabrication using CLIP technology.