3D Printing Pharmaceutical Preparation Technologies Based On Digital Light Processing

Pharmaceutical preparation technologies can be used to develop pharmaceutical preparations with good curative effects and high safety.They play a key role in the process of drug development and provide important technical support for the preparation of new pharmaceutical preparations.3D printing technology provides a new means for the development of advanced pharmaceutical preparation technologies.3D printing technology refers to a rapid prototyping technology that directly converts digital models into 3D constructs via layer-by-layer accumulation.Among them,DLPbased 3D printing technology attracts wide attention due to its advantages such as high printing resolution,fast printing speed,and no obvious damage to cells during the printing process.At present,oral,injection,and even surgery are common methods of administration of pharmaceutical preparations.As an efficient treatment method,minimally invasive treatment can reduce the wound surface of drug administration,improve the adaptability of patients,and reduce the risk of complications such as infection,adhesions,and scars.It has become an important direction of medical development.DLP-based 3D printing technology can customize functional multi-scale pharmaceutical preparations,providing new means and key technical support for the realization of minimally invasive treatment.So,it is of great scientific and clinical significance to develop DLP-based 3D printing pharmaceutical preparation technologies for the field of minimally invasive medicine.This paper developed DLPbased 3D printing pharmaceutical preparation technologies to prepare injectable cell preparations for minimally invasive tissue repair and reconstruction,and fabricate coated CMNA for minimally invasive transdermal drug delivery.It is expected to promote the development of minimally invasive medicine.The specific research contents are as follows:(1)3D printing injectable cell preparation technology for minimally invasive tissue repair and reconstructionCurrently,autologous or allogeneic tissue/organ transplantation is the main method for the treatment of large-scale tissue/organ defects.However,there are many problems with this method such as donor shortage and immune rejection.As a new type of medicine,cellular drugs are promising for treating tissue/organ defects.However,direct injection of cell suspension tends to reduce cell viability in the body.At the same time,it is difficult to precisely control the spatial distribution of cells.DLP3 D printing technology can be combined with cells,biological materials,and biological factors to prepare tissue constructs with complex structures,providing an important method for fabricating personalized artificial tissues/organs.DLP 3D printing technology has potential application in the fields of tissue repair and reconstruction.As a common DLP 3D printing ink,Gel MA can be photocured to form hydrogels that have a 3D network structure similar to natural tissues and good biocompatibility.However,the complex and large-scale 3D printed tissue constructs,which use Gel MA hydrogels as a cell scaffold,always show poor injectability.Invasive surgery is the major way for them to implant into the body,which cannot meet the clinical needs of minimally invasive treatment.At the same time,the dense polymer network in Gel MA hydrogels cannot provide a good microenvironment for readjusting the biological functions of cells.Considering the limitations of the above-mentioned Gel MA hydrogels for 3D printing and the great demand for clinical minimally invasive treatments,this paper proposed a new strategy for tissue construction and in vivo delivery.Based on the principle of “phase separation,self-assembly,photocuring”,we established a new technology for preparing p-Gel MA hydrogels with microgel-packing structures.Furthermore,by combining this technology with DLP 3D printing,the external earlike cartilage tissue construct was prepared and delivered into the body as an injectable cell preparation for the minimally invasive repair and reconstruction of external ear cartilage tissue.First,we proposed new technology for preparing p-Gel MA hydrogels.By optimizing the formula,a mixture solution of Gel MA and Pluronic F127 with a mass ratio of 3:2(G/F 3:2)was established as a 3D printing ink.During the mixing process,the Gel MA pre-gel solution and the Pluronic F127 solution undergone phase separation,and the Gel MA self-assembled to form microdroplets due to mechanical mixing.Subsequently,the 3D printing ink was photocured,and the water-soluble Pluronic F127 was removed by soaking,thereby obtaining a p-Gel MA hydrogel with microgelpacking structures.Compared with standard Gel MA hydrogels that only had nanopores and were easily broken,the p-Gel MA hydrogels had good shape memory characteristics and could be used for minimally invasive injections.Next,we focused on comparing the biological functions of cells in standard Gel MA hydrogels and pGel MA hydrogels.According to the results,p-Gel MA hydrogels showed higher cell survival rate,faster proliferation,more obvious spreading,more free migration and better maintenance of cell function compared with standard Gel MA hydrogels.More importantly,the injection process did not reduce the viability of cells in p-Gel MA hydrogels,which laid the foundation for further realization of 3D printed injectable cell preparations.Finally,based on the p-Gel MA bioink,we used high-precision DLP 3D printing to prepare the p-Gel MA external ear-like tissue constructs loaded with chondrocytes.Subsequently,the tissue constructs were delivered as injectable cell preparations to nude mice subcutaneously to evaluate their chondrification in vivo.The samples were harvested after one month.H&E staining,safranin-O staining,toluidine blue staining,and immunohistochemical staining were used for histological evaluation.The results show that,compared with standard Gel MA tissue constructs implanted by invasive surgery,the injectable p-Gel MA tissue constructs contained richer new cartilage matrix and had stronger biomechanical properties.It indicated that the 3D printed injectable cell preparations based on p-Gel MA hydrogels had excellent ability to promote tissue regeneration.In short,based on the principle of "phase separation,self-assembly,photocuring" and combined with DLP 3D printing,we established a new technology for preparing injectable cell preparations.This technology had broad application prospects in the fields of minimally invasive tissue repair and reconstruction.(2)3D printing customized microneedle array technology for minimally invasive transdermal drug deliveryTDD is another alternative to oral or injection administration.It can avoid gastrointestinal metabolism and first-pass effects of liver,lessen patient pain,and reduce the risk of infection.However,due to the barrier function of the stratum corneum of the skin,most hydrophilic or macromolecular drugs are difficult to effectively penetrate the skin.As an efficient and painless transdermal drug delivery tool,microneedles can penetrate the stratum corneum of skin and generate a large number of temporary microchannels,thereby significantly improving the penetration rate of drugs.At present,the micro-template method is a common preparation method for microneedles.However,this method requires a complicated manufacturing process,high cost,and poor flexibility of microneedle parameter control,which is difficult to meet the needs of personalized treatment.3D printing technology provides an important method for preparing CMNA,but the existing microneedle 3D printing technologies fail to fast construct high-quality CMNAs without “step effect” in a very short time.Therefore,there is still a great challenge to quickly customize high-quality microneedle arrays.In this paper,based on the principle of DLP,we proposed new SOPL technology for rapid customization of high-quality microneedle arrays.Furthermore,the coated CMNA prepared by dip-coating method could be used for minimally invasive transdermal drug delivery.By co-delivering drugs and UCNPs,it was expected to achieve in vivo information storage at the same time as transdermal drug delivery.Considering the lack of technology for rapid customizing high-quality microneedle arrays,we proposed a fast and continuous 3D printing technology(SOPL).This technology used the digital light projected by the DMD chip to have a specific light intensity distribution in the photosensitive material.The light intensity gradually weakened from the center of the focal plane to the outside,and the photosensitive resin could occur precise "static" photopolymerization under specific printing parameters.Thus,the integral forming could realize rapid customization of high-quality CMNA in a few seconds.During the formation of the microneedle,the height of the microneedle could be flexibly adjusted by changing parameters such as exposure time,exposure power,and microneedle bottom area.Based on SOPL technology,we used photosensitive resin to prepare a series of CMNA with different bottom shapes,heights,angles,and distributions.Next,rhodamine was used as the model drug to prepare drugcoated CMNA by dip-coating method.By adjusting the dip-coating times and the shapes of microneedles,the drug loading of CMNA could be significantly increased.The in vitro drug release results showed that the coated CMNA could quickly release model drugs in PBS.Furthermore,we verified that CMNA had sufficient mechanical properties to easily penetrate the skin and produce temporary microchannels of the corresponding shape.Besides,the skin could heal quickly within 30 minutes.After applying the coated CMNA to the back skin of mice,a large amount of rhodamine was released and diffused into the skin,indicating that the coated CMNA could be used for minimally invasive transdermal drug delivery.Finally,we proposed an integrated strategy for minimally invasive transdermal drug delivery and in vivo information storage.The information-encoded CMNA was prepared via SOPL technology,to codeliver rhodamine mode drugs and UCNPs,which could create an untouchable and concealed fluorescent dot matrix in the skin.Only when irradiated by NIR light,UCNPs were excited and emitted visible blue fluorescence,thus presenting a complete and clear information pattern on the skin surface.In short,we proposed a SOPL technology for rapid customizing high-quality CMNA,which could be used for minimally invasive transdermal drug delivery.Combined with UCNPs,we developed an integrated strategy for transdermal drug delivery and in vivo information storage,which possessed the advantages of convenient operation,strong concealment and large information capacity.In summary,based on the principle of "phase separation,self-assembly,photocuring",this paper established a new technology for preparing p-Gel MA hydrogels with microgel-packing structures.The p-Gel MA hydrogels had good injectability and biocompatibility.Subsequently,the p-Gel MA was used as bioink,and injectable external ear-like chondrocyte preparations were prepared via DLP 3D printing for minimally invasive tissue repair and reconstruction of external ear cartilage tissue.This research provided a new idea for the design of new photocurable bioink and a novel method for minimally invasive tissue repair and reconstruction.In addition,based on DLP principle,this paper proposed a fast and continuous SOPL technology.It could quickly customize high-quality CMNA in a few seconds without the need for traditional layer-by-layer printing.Subsequently,rhodamine was used as a model drug to loaded into CMNA,which could be used for minimally invasive transdermal drug delivery.Furthermore,by co-delivering drugs and UCNPs through CMNA,it was expected to realize in vivo information storage at the same time as minimally invasive transdermal drug delivery.This research provided new technology for rapid customization of high-quality microneedle arrays,and an integrated strategy for the simultaneous realization of minimally invasive transdermal drug delivery and in vivo information storage.To further respond to the major needs of clinical minimally invasive treatment,the above researches developed the DLP-based 3D printing pharmaceutical preparation technologies,which were expected to further promote the research development of minimally invasive medicine.