In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment-specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double-network hydrogel scaffold produced via 3D printing with tissue-specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D-printed microenvironment-specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM-based microenvironment-specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell-free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.

3D Printing of Microenvironment-Specific Bioinspired and Exosome-Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration.

Additive manufacturing (AM), which is based on the principle of layer-by-layer shaping and stacking of discrete materials, has shown significant benefits in the fabrication of complicated implants for tissue engineering (TE). However, many native tissues exhibit anisotropic heterogeneous constructs with diverse components and functions. Consequently, the replication of complicated biomimetic constructs using conventional AM processes based on a single material is challenging. Multi-material 3D and 4D bioprinting (with time as the fourth dimension) has emerged as a promising solution for constructing multifunctional implants with heterogeneous constructs that can mimic the host microenvironment better than single-material alternatives. Notably, 4D-printed multi-material implants with biomimetic heterogeneous architectures can provide a time-dependent programmable dynamic microenvironment that can promote cell activity and tissue regeneration in response to external stimuli. This paper first presents the typical design strategies of biomimetic heterogeneous constructs in TE applications. Subsequently, the latest processes in the multi-material 3D and 4D bioprinting of heterogeneous tissue constructs are discussed, along with their advantages and challenges. In particular, the potential of multi-material 4D bioprinting of smart multifunctional tissue constructs is highlighted. Furthermore, this review provides insights into how multi-material 3D and 4D bioprinting can facilitate the realization of next-generation TE applications. This article is protected by copyright. All rights reserved.

Multi-Material 3D and 4D Bioprinting of Heterogeneous Constructs for Tissue Engineering.


 Despite the considerable advancements in fabricating polymeric-based scaffolds for tissue engineering, the clinical transformation of these scaffolds remained a big challenge because of the difficulty of simulating native organs/tissues' microenvironment. As a kind of natural tissue-derived biomaterials, decellularized extracellular matrix (dECM)-based scaffolds have gained attention due to their unique biomimetic properties, providing a specific microenvironment suitable for promoting cell proliferation, migration, attachment, and regulating differentiation. The medical applications of dECM-based scaffolds have addressed critical challenges, including poor mechanical strength and insufficient stability. For promoting the reconstruction of damaged tissues or organs, different types of dECM-based composite platforms have been designed to mimic tissue microenvironment, including by integrating with natural polymer or/and syntenic polymer or adding bioactive factors. In this review, we summarized the research progress of dECM-based composite scaffolds in regenerative medicine, highlighting the critical challenges and future perspectives related to the medical application of these composite materials.

Decellularized extracellular matrix-based composite scaffolds for tissue engineering and regenerative medicine

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach. 

Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy

Human cartilage tissue can be categorized into three types: hyaline cartilage, elastic cartilage and fibrocartilage. Each type of cartilage tissue possesses unique properties and functions, which presents a significant challenge for the regeneration and repair of damaged tissue. Bionics is a discipline in which humans study and imitate nature. A bionic strategy based on comprehensive knowledge of the anatomy and histology of human cartilage is expected to contribute to fundamental study of core elements of tissue repair. Moreover, as a novel tissue-engineered technology, 3D bioprinting has the distinctive advantage of the rapid and precise construction of targeted models. Thus, by selecting suitable materials, cells and cytokines, and by leveraging advanced printing technology and bionic concepts, it becomes possible to simultaneously realize multiple beneficial properties and achieve improved tissue repair. This article provides an overview of key elements involved in the combination of 3D bioprinting and bionic strategies, with a particular focus on recent advances in mimicking different types of cartilage tissue. 

The core elements of bionic bioprinting for cartilage tissue engineering recent advances in 3D bioprinted cartilage-mimicking constructs for applications in tissue engineering

Background: The accuracy of existing devices for measuring knee laxity is adversely affected by examiner reliability. Purpose: To compare the accuracy of a novel automatic knee arthrometer (AKA) to that of the KT-2000 arthrometer for measuring knee laxity after anterior cruciate ligament (ACL) ruptures. Study Design: Cohort study; Level of evidence, 2. Methods: We measured anterior displacement and the anterior displacement difference (ADD) at 134 N of anterior force in 221 healthy volunteers and 200 patients with ACL ruptures. All trials were performed by the same 2 examiners. We first analyzed the effects of examiner, side assessed, and device type using the intraclass correlation coefficient (ICC), t test, and F test. We then used the receiver operating characteristic curve to compare the diagnostic value of the measurements between devices. Results: In repeated measurements for a single healthy volunteer, there were no differences in the variance of the measurements between sides according to the AKA (standard deviation of right vs left knee for examiner A: 0.43 vs 0.58 mm, respectively [P = .39]; for examiner B: 0.49 vs 0.77 mm, respectively [P = .81]), while the KT-2000 measurements showed differences (standard deviation of right vs left knee for examiner A: 1.47 vs 0.80 mm, respectively [P = .02]; for examiner B: 1.78 vs 0.91 mm, respectively [P = .01]). The ADD assessed by the AKA was not significantly different between examiners A and B (0.50 vs 0.75 mm, respectively; P = .27; ICC = 0.83), but the KT-2000 showed a difference (1.07 vs 2.01 mm, respectively; P = .01; ICC = 0.55). The ADD of 20 healthy volunteers assessed by the AKA was less than that by the KT-2000 (0.98 vs 1.41 mm, respectively; P = .04). When comparing the diagnostic value of the 2 devices in the sample of 200 patients with ACL ruptures and 200 healthy controls, the area under the receiver operating characteristic curve for the AKA was larger than that for the KT-2000 (0.93 vs 0.87, respectively; P ≤ .01), and the threshold values were 1.75 and 2.73 mm, respectively. Conclusion: The AKA can be used to determine the degree of knee laxity in ACL injuries and to provide indications for treatment.

Reliability of a Novel Automatic Knee Arthrometer for Measuring Knee Laxity After Anterior Cruciate Ligament Ruptures

Targeting aging with the healthy skeletal system: The endocrine role of bone.

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3D Printing of Microenvironment-Specific Bioinspired and Exosome-Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration.

Reliability of a Novel Automatic Knee Arthrometer for Measuring Knee Laxity After Anterior Cruciate Ligament Ruptures

Targeting aging with the healthy skeletal system: The endocrine role of bone.